MTMR fosfataasiperhe: . PIKFYVE ja MTMR3 tuottavat PI(5)P

https://www.ncbi.nlm.nih.gov/pubmed/17917119

MTMR FOSFATAASEJA ON ISO PERHE.
(MTMR3 omaa  FYVE domaanitkin . katson sen tunnetut ja suositellut nimet)


 Otan tästä lähdetietoa. ihmiselläkin on niitä 14 proteiinia ja niistä kahdeksan  ovat katalyyttiseti aktiivea fosfataasena  ja kuusi katalyyttisesti inaktiivia.  Aktiiveilla MTMR-jäsenillä on kaikilla  fosfataasiaktiivisuutta  PI3P ja PI(3,5)P2  fosfoinositidilajeja kohtaan.  (Tässä käytetään  uutta termiäkin pylofosfoinositidit, PPIn)  - ja  tämä spesifisyys viittaisi intrasellulaariseen  liikenteeseen ja kalvohomeostaasiin.  MTMR- lyhennys tarkoitta Myotubulariinin liittyvien  fosfolipidien  fosfataasi 

Mol Neurobiol. 2007 Jun;35(3):308-16.

• Myotubularin-related (MTMR) phospholipid phosphatase proteins in the peripheral nervous system. Bolis A¹, Zordan P, Coviello S, Bolino A. Abstract Myotubularin-related proteins (MTMRs) constitute a broad family of ubiquitously expressed phosphatases with 14 members in humans, of which eight are catalytically active phosphatases, while six are catalytically inactive. Active MTMRs possess 3-phosphatase activity toward both PtdIns3P and PtdIns(3, 5)P 2 poliphosphoinositides (PPIn), suggesting an involvement in intracellular trafficking and membrane homeostasis.

Näitten MTMR- fosfataasien joukossa MTMR2 ja MTMR13 eivät  kata toistensa funktioita  hermossa.  Jommankumman puute aiheuttaa CMT tyyppi 4B1 ja B2 neuropatiat vastaavasti. Tyypillistä on  demyelinaatio  ja  poikkeukselliset myeliinipoimut.
MTMR2 fosfolipidifosfataasi sattaa säädellä  kalvohomeostaasissa  taaphtumia Schwannin soluissa  hermon postnataalin kehittymisen aiakna.   Artikkeli valaisee lähinnä MTMR2 ja MTMR13 kannalta  näitä MTMR perheen jsäeniä. solunsisäisiä

•  Among MTMRs, catalytically active MTMR2 and inactive MTMR13 have a nonredundant function in nerve. Loss of either MTMR2 or MTMR13 causes Charcot-Marie-Tooth type 4B1 and B2 neuropathy, respectively, characterized by demyelination and redundant loops of myelin known as myelin outfoldings. In Mtmr2-null mouse nerves, these aberrant foldings occur at 3-4 weeks after birth, a time when myelination is established, and Schwann cells are still elongating to reach the final internodal length. Moreover, Mtmr2-specific ablation in Schwann cells is both sufficient and necessary to provoke CMT4B1 with myelin outfoldings. MTMR2 phospholipid phosphatase might regulate intracellular trafficking events and membrane homeostasis in Schwann cells during postnatal nerve development. In this review, we will discuss recent findings on the MTMR family with a major focus on MTMR2 and MTMR13 and their putative role in Schwann cell biology.

PMID:

17917119

[Indexed for MEDLINE]

• MTMR3 on ZFYVE10

https://www.ncbi.nlm.nih.gov/gene/8897

Also known as ZFYVE10; FYVE-DSP1

Summary This gene encodes a member of the myotubularin dual specificity protein phosphatase gene family. The encoded protein is structurally similar to myotubularin but in addition contains a FYVE domain and an N-terminal PH-GRAM domain. The protein can self-associate and also form heteromers with another myotubularin related protein. The protein binds to phosphoinositide lipids through the PH-GRAM domain, and can hydrolyze phosphatidylinositol(3)-phosphate and phosphatidylinositol(3,5)-biphosphate in vitro. The encoded protein has been observed to have a perinuclear, possibly membrane-bound, distribution in cells, but it has also been found free in the cytoplasm. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008] Expression Ubiquitous expression in bone marrow (RPKM 20.3), testis (RPKM 13.1) and 25 other tissues See more Orthologs mouse all

Related articles in PubMed

1. Myotubularin-related phosphatase 3 promotes growth of colorectal cancer cells. Zheng B, et al. ScientificWorldJournal, 2014. PMID 25215329, Free PMC Article
2. Expression, purification, crystallization and preliminary crystallographic analysis of human myotubularin-related protein 3. Son JY, et al. Acta Crystallogr F Struct Biol Commun, 2014 Sep. PMID 25195900, Free PMC Article
3. Brief Report: identification of MTMR3 as a novel susceptibility gene for lupus nephritis in northern Han Chinese by shared-gene analysis with IgA nephropathy. Zhou XJ, et al. Arthritis Rheumatol, 2014 Oct. PMID 24943867, Free PMC Article
4. Modulation of local PtdIns3P levels by the PI phosphatase MTMR3 regulates constitutive autophagy. Taguchi-Atarashi N, et al. Traffic, 2010 Apr. PMID 20059746
5. Analysis of phosphoinositide binding domain properties within the myotubularin-related protein MTMR3. Lorenzo O, et al. J Cell Sci, 2005 May 1. PMID 15840652

See all (51) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. Data suggest MTMR3 has multiple functions in regulation of autophagy; one mechanism appears to be direct interaction between MTMR3 and mTORC1 (MTOR, mLST8, raptor) which inhibits phosphorylation activity of mTORC1; MTMR3 is localized to Golgi apparatus.
2. the rs713875 IBD risk polymorphism increases MTMR3 expression, which modulates pattern recognition receptor (PRR)-induced outcomes, including increased induced caspase-1 activation
3. myotubularin-related protein 3 and myotubularin-related protein 4 may act as a bridge between CEP55 and polo-like kinase 1, ensuring proper CEP55 phosphorylation and regulating CEP55 recruitment to the midbody.
4. cloning, expression, purification and crystallization of human myotubularin-related protein 3 encompassing the PH-GRAM and the phosphatase catalytic domain are reported
5. These results indicate that MTMR3 may play an important role in the progression of CRC and suggest that siRNA mediated silencing of MTMR3 could be an effective tool in CRC treatment.
6. Our results suggest that the MTMR3 gene is shared between IgA nephropathy and lupus nephritis in the northern Chinese population, further highlighting the role of autophagy in systemic lupus erythematosus.
7. Data suggest MTMR3, PIKFYVE (phosphoinositide kinase FYVE), and their product phosphatidylinositol 5-phosphate are involved in activation of RAC1 (rho family small GTP binding protein); this process regulates migration/invasion of carcinoma/sarcoma.
8. Production of phosphatidylinositol 5-phosphate via PIKfyve and MTMR3 regulates cell migration.
9. A phylogenetic study revealing co-evolution of myotubularins with PI 3-kinase class III complex
10. MTMR3 shares similar phosphatase activity and substrate specificity with its homologous proteins MTM1 and MTMR3
11. 
    

    MTMR3  Preferred Names

    myotubularin-related protein 3

    Names

    FYVE (Fab1 YGLO23 Vsp27 EEA1 domain) dual-specificity protein phosphatase

    FYVE domain-containing dual specificity protein phosphatase 1

    phosphatidylinositol-3,5-bisphosphate 3-phosphatase

    phosphatidylinositol-3-phosphate phosphatase

    zinc finger FYVE domain-containing protein 10

    zinc finger, FYVE domain containing 10

    NP_066576.1

    • EC 3.1.3.48

    • EC 3.1.3.64

    • EC 3.1.3.95

    NP_694690.1..

     

    Conserved Domains (3) summary

    cd13341
    Location:23 → 116

    PH-GRAM_MTMR3; Myotubularian (MTM) related 3 protein (MTMR3) Pleckstrin Homology-Glucosyltransferases, Rab-like GTPase activators and Myotubularins (PH-GRAM) domain

    cd15732
    Location:1115 → 1175

    FYVE_MTMR3; FYVE domain found in myotubularin-related protein 3 (MTMR3) and similar proteins

    pfam06602
    Location:127 → 523

    Myotub-related; Myotubularin-like phosphatase domain

PI(3)P , PI(3,5)P ja niiden fosfataasi MTMR2- mitä ne tekevät?

https://www.ncbi.nlm.nih.gov/pubmed/20410104
lipositolifosfolipideille (PI), inositidirakenteille, joissa on 3- asemassa fosfaatti,  on oma fosfaataasinsa ja se  kohdistuu  tähän 3-aseman fosfaattiin poistaen sen.

MTMR2 entsyymi on tällainen 3-fosfataasispesifinen fosfoinositideille PI(3)P ja PI(3,5)P2 ja näitä molempia esiintyy endosomeissa. 

Jos  Schwannin soluissa esiintyy  MTMR2-mutaatioita ja tämä fosfataasi ei toimi normaalisti, seuraa  vakavaa demyelinisoivaa perifeeristä neuropatiaa, joka tunnetaan   CharcotMmarie-Tooth taudin tyyppinä 4B1.
 https://www.semanticscholar.org/paper/Myotubularin-Related-(MTMR)-Phospholipid-Proteins-Bolis-Zordan/408e175c01fe779c717510b64c096af474fe5d3e/figure/4

Tätä MTMR2 fosfataasia esiintyy perifeerisessä ja keskushermostossa. , keskushermoston taholta tulevia oireita ei ole aiemmin selvitelty.

 Tässä artikkelissa kerrotaan, että  MTMR2-fosfataasia  paikallistuu keskushermoston stimulatorisiin synapseihin ja se tekee suoraa interaktiota  PSD-95  postsynaptiseen  tukirankaproteiiniin, jota on  näissä synapseissa runsaasti.

MTMR2 poistogeenisyys vaikutti stimuloivien synapsien tiheyden  ja toiminnan alenemista. Myös EEA1-positiivisuus dendriittihaaroissa  varhaisissa endosomeissa  väheni, mutta lisääntyi solusooman alueella.

MTMR2:n vaimentaminen edisti  endosomaalisen kuorman,AMPAr-eseptoreiden GluR2 alayksiköiden   endosytoosia,  mutta ei edistänyt   reseptorien uudelleen kierrätystä. Lisäksi havaittiin, että  Lamp1-positiivisiin  myöhäisiin endosomeihin/lysosomeihin  kertyneet GluR2 reseptorialayksilöt  lisääntyivät solusoomassa, mutta ei dendriiteissä.

 Tulokset viittaavat siihen, että  PSD-95:n kanssa interaktion tekevä MTMR2 fosfataasi  antaa oman osansa  stimuloivien synapsien ylläpitoon estämällä  liiallista  endosomien muodostusta ja   lysosomaaliseen hajoitukseen johtavaa endosomaalista  tietä.

Alla olevassa linkissä on kuva missä  reseptorin  endosomaalitie näkyy, myös uudelleenkierrrätyslinkki.kuvan oiekassa laidassa.


https://www.researchgate.net/figure/Model-for-a-role-of-cPLA-2-a-in-LTD-induction-AMPA-and-PMA-can-mimic-the-stimuli-that_fig9_23181093

• J Neurosci. 2010 Apr 21;30(16):5508-18. doi: 10.1523/JNEUROSCI.4283-09.2010.The phosphoinositide 3-phosphatase MTMR2 interacts with PSD-95 and maintains excitatory synapses by modulating endosomal traffic.Lee HW¹, Kim Y, Han K, Kim H, Kim E. Abstract

• MTMR2 is a 3-phosphatase specific for the phosphoinositides PI(3)P and PI(3,5)P(2), which are mainly present on endosomes. Mutations in the MTMR2 gene in Schwann cells lead to a severe demyelinating peripheral neuropathy known as Charcot-Marie-Tooth disease type 4B1. MTMR2 expression is also detected in peripheral and central neurons, but neural functions of MTMR2 remain unclear. Here, we report that MTMR2 is localized to excitatory synapses of central neurons via direct interaction with PSD-95, a postsynaptic scaffolding protein abundant at excitatory synapses. Knockdown of MTMR2 in cultured neurons markedly reduces excitatory synapse density and function. This effect is rescued by wild-type MTMR2 but not by a mutant MTMR2 lacking PSD-95 binding or 3-phosphatase activity. MTMR2 knockdown leads to a decrease in the intensity of EEA1-positive early endosomes in dendrites but increases the intensity in the cell body region. Moreover, MTMR2 suppression promotes endocytosis, but not recycling, of the GluR2 subunit of AMPA receptors, which is an endosomal cargo. In addition, colocalization of internalized GluR2 with Lamp1-positive late endosomes/lysosomes is enhanced in the cell body area but not in dendrites. These results suggest that PSD-95-interacting MTMR2 contributes to the maintenance of excitatory synapses by inhibiting excessive endosome formation and destructive endosomal traffic to lysosomes.
• PMID: 20410104 DOI: 10.1523/JNEUROSCI.4283-09.2010

Artikkeli vuodelta 2002. FYVE finger ja EEA1

https://www.sciencedirect.com/science/article/pii/S0014579301033087
Valmis artikkeli, josta  SITAATTI netistä,  löytyi tästäkin  aiheesta.

Minireview

The phosphatidylinositol 3-phosphate-binding FYVE finger

Edited by Gianni Cesareni and Mario Gimona

Author links open overlay panel

 HaraldStenmark^aReinAasland^bPaul C.Driscoll^cd

https://doi.org/10.1016/S0014-5793(01)03308-7Get rights and content

Under an Elsevier user license 

Tiivistelmä,  Suomennosta

FYVE sinkkisormidomeeni on konservoitunut hiivasta ihmiseen ( 27 proteiinia). Sen  funktiona on  sytosolisten proteiinien  rekrytoiminen  kalvoon PI(3)P-lipidivälitteisesti ja tätä havaitaan  tapahtuvan pääasiassa endosomeissa. Artikkeli on katsaus , joka valaisee  FYVE finger-proteiinien kohdentamista PI(3)P-lipidiä sisältäviin kalvoihin ja millä tavalla nämä proteiinit  toimivat solufunktioiden säätelyssä apuna.

•  Abstract
  The FYVE zinc finger domain is conserved from yeast (five proteins) to man (27 proteins). It functions in the membrane recruitment of cytosolic proteins by binding to phosphatidylinositol 3-phosphate (PI3P), which is found mainly on endosomes. Here we review recent work that sheds light on the targeting of FYVE finger proteins to PI3P-containing membranes, and how these proteins serve to regulate multiple cellular functions.

 https://ars.els-cdn.com/content/image/1-s2.0-S0014579301033087-gr3.jpg

 

1. Download full-size image

 EEA1 FYVE sinkkisormen ja siihen liittyvän coiled -coil -alueen kiderakenne kuvana. 
Tämän rakenteen homodimeerinen luonne eroaa jyrkästi siitä isoloidusta EEA1 FYVE finger -havainnosta, joka on saatu NMR- observaatioissa. 
Tässä uudessa struktuurissa on luotuna  dimeeri-interfaasipinta helikaaliselle alueelle kahden  FYVE-fingerin kesken koko pituudelta.  kaksi PI(3)P molekyyliä  on sitoutuneena tavalliseen  kalvopintaan päinvastaiseen suuntaan helikaalisen rungon suhteen ja oletettu FYVE-finger  kalvopinnalla  on enemmän esillä kuin mitä  aiemmin oletettiin  päätyosasta. Lyhyt linkkiosa coiled coil-domeenin ja FYVE finger segmenttien  välilläon  rakenteellisesti järjestäytynyttä ( alfa-helix) ka sen jakson amonohappot autavat stabiloimaan  ligandin koordinaatiopiiriä. NMR-tiedon tulkinnasta on oletettu  FYVE finger- dimerisaatiota, muta myös ligandispesifistä  FYVE-fingerstruktuurin muutosta. Analysoitaessa EEA1-kiteen rakennetta  sellaiselle muutokselle olisi tiukat rajansa ja ne rajoittuisivat vain muutaman sivuketjun rotameerin kääntelyyn. PI(3)P pääryhmän kiinnittäminen  vaatii   kaikki kolme konservoitua motiivia . 3-Fosfaatti koordinoituu baasisilla  R(R/K)C ja VC motiivien  baasisilla  sivuketjuilla   ( interaktioaminohapot alleviivattu) - jälkimmäinen käyttää vesimolekylisil
taa. Inositolin 4_OH, 5-OH/ 6-OH ryhmät  antavat H-siltaa   R(R/K) HCR ja Wxx-motiiveille. 
PI(3)P - molekyylin  1-fosfaatti  tekee interaktion  (R/K )HHCR motiivin ensimmäisen arginiinin R  kanssa. Toinen baasinen tähde R( )HHCR- motiivista muodsotaa "toisen koordinaatiokuori"-interaktion  toisen FYVE -finger aminohappotähteen kanssa ja se vahvistaa suoria kontakteja. Mielenkiintoinen seikka on, että osallistumalla suoraan interaktioon ligandin pääryhmän hydroksyylien (OH) kanssa sivuketjut blokeeraavat tehokkaasti nämä sijaintikohdat , joihin voisi sijoitautua alternatiivisia ligandeja joisa on  4- ja 5- aseman fosfaatteja inositolirenkaassa- tällä selittyy osittain FYVE-fingerin ligandiselektiivisyys  PI(3)P lipidiä kohtaan.. 
PI(3)P lipidimuotoa vastaava vesiliukoinen inositolifosfaatti on Ins (1,3)P2 ja sen  sidokset  on myös tutkittu  EEA1:n suhteen.  Toinen kuva.  Siitä  selviää FYVE finger sekvenssin konservoitumisen   merkitys  ligandispesifisyyden suhteen ja myös merkitys mutaatioissa.  Alternativiisten fosfoinositidien ligandimuotojen  olisi orientoiduttava toisella tavalla ja  tällöin  olisi merkittävää alenemista sitoutumisien affiniteetissa. Alimopana on liukoisen  inositolidifosfaatin  ja EEA1:n  väliset  sitoutumiset  kuvattu.

1. Fig. 3. Crystal structure of the EEA1 FYVE finger and adjacent coiled-coil region. The homodimer nature of this structure contrasts with the NMR observations of the isolated EEA1 FYVE finger. Notably in the new structure, the dimer interface created with the coiled-coil region is contiguous with the contact between the two FYVE fingers. The two PI3P molecules are bound on a common surface directly opposite the coiled-coil stalk and the putative arrangement of the FYVE fingers on the membrane surface is more ‘prone’ than ‘end on’ as previously anticipated. The short linking region between the coiled-coil and FYVE finger segments is structurally ordered (forming an α-helix) and residues in this segment assist the stabilisation of the ligand coordination sphere. The interpretation of the NMR data had anticipated FYVE finger dimerisation, but had also suggested ligand-dependent conformational changes of the FYVE finger [16]. Analysis of the EEA1 crystal structure would appear to put strict limits upon any such change, limited perhaps to a few side chain rotamer perturbations [18]. The ligation of the PI3P headgroup involves all three conserved signature motifs (see Fig. 4) [18]. The 3-phosphate is coordinated by basic side chains of the R(R/K)C and VC motifs (interacting residues underlined) – the latter using a bridging water molecule. The inositol 4-OH and 5-OH/6-OH groups donate H-bonds to the R(R/K)HCR and Wxx motifs respectively. The 1-phosphate interacts with the first arginine of the (R/K)HHCR motif. The second basic residue of the R()HHCR motif makes ‘second coordination shell’ interactions with other FYVE finger residues that reinforce the direct contacts. Interestingly, side chains involved in direct interaction with the ligand headgroup hydroxyls effectively block the locations that would be occupied by alternative ligands containing phosphates at the 4- or 5-position of the inositol ring, an observation that goes part way to explain the ligand selectivity of the FYVE finger.
2.  In all, six residues contact the  (soluble)  Ins(1,3) P2   group, providing a detailed and convincing rationalisation of FYVE finger sequence conservation, ligand specificity, and the results of previously reported mutagenesis studies [13,14]. Alternative phosphoinositide (PtdIns, PI)  ligands would have to bind in a different orientation and would suffer a significant reduction in binding affinity.

https://ars.els-cdn.com/content/image/1-s2.0-S0014579301033087-gr4.jpg

(Huom.
 Inositolitiede  alkoi edistyä 2001 jälkeen ja myös Chalmerissa on tutkittu ,  (Maria Tûrk) inositolirakenteita. Se on vaikeasti tutkittava molekyyli.
 


 Suom. Näissä tutkimuksissa huomattiin että FYVE-finger  sitoutui paljon suuremmalla affiniteetilla kalvoon liittyneeseen PI3P  lipidiin kuin sitä vastaavaan vesiliukoiseen liukoiseen analogiin inositoli-1,2-difosfaattiin. (IP2).  lipidimuotoista PI(3) löytyy lähinnä endosomeista. Kuitenkin vain harva FYVE finger ( endofin, FENS-1) sitoutuu PI3P- lipidiin riittävällä affiniteetilla toimiakseen autonomisina kalvoon kohdentuvina domeeneina. Muissa tapauksissa (kuten HRS ESCRT-komponentissa  ja EEA1:ssä)  tehokkaaaseen kalvoon sitoutumsieen tarvitaan vielä joitain lisädomeeneja.  EEA1:llä coiled -coil saataa lisätä  sen aviditeettia  PI3P-sisältöisiin endosomikalvoihin. Interaktio Rab5:n kanssa saatta edelleen stabilisoida  interaktiota tai kohdentaa EEA1.n Rab5:ttä sisältäviin kalvodomeeneihin.  Muutamia FYVE fingerproteiineja ei edes tavata endosomeista (MTMR3, Fgd1 ja DFCP1/TAFF1-(Lisäys:  tätä viimeksimainittua kyllä löytyy omegasomesita, trimosomeista).  Oletettiin, että  näiden muiden proteiiien FYVE fingerit eivät olleet affiniteetiltaan  riittäviä toimiakseen endosomiin kohdentavana domaanina yksinään ja niiden funktionaalista  relevanssia  PI3P:n sitomisessa ei oltu vielä 2002 selvitetty.

• Recent progress has revealed the full array of FYVE finger proteins in humans and other organisms, and the structural basis for the interaction of FYVE fingers with PI3P has been characterised. The proposed insertion of the hydrophobic ‘turret loop’ of the FYVE finger into the membrane (Fig. 3) is consistent with the fact that FYVE fingers bind with much higher affinity to membrane-associated PI3P than to its soluble analogues [14,43]. Given that PI3P is mainly found on endosomes, it is not surprising that most FYVE finger proteins are associated with these organelles. However, only a few FYVE fingers (e.g. those of endofin and FENS-1) bind to PI3P with sufficient affinity to function as autonomous membrane targeting domains [37,44]. In other cases (e.g. EEA1 and Hrs), additional domains are required for efficient membrane binding. Coiled-coil dimerisation of EEA1 may increase its avidity for PI3P-containing endosome membranes [45], and an interaction with Rab5 may further stabilise the interaction or target EEA1 to Rab5-containing membrane domains. A few FYVE finger proteins (e.g. MTMR3, Fgd1 and DFCP1/TAFF1) are not found on endosomes [39,46–49]. Presumably, the FYVE fingers of these proteins have too low affinity for PI3P to function as endosome targeting domains, and the functional relevance of their PI3P binding remains elusive.

Kiinnostava FYVE domeeni. Myös TP53 omaa FYVE-domeenin.

https://www.ncbi.nlm.nih.gov/gene/7157
 TP53    (Kr.17p13.1) , p53

Also known as  P53; BCC7; LFS1; TRP53

 

Summary  This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

Expression Ubiquitous expression in spleen (RPKM 13.2), lymph node (RPKM 13.1) and 25 other tissues See more Orthologs  mouse all

Preferred Names

cellular tumor antigen p53

Names

antigen NY-CO-13

mutant tumor protein 53

p53 tumor suppressor

phosphoprotein p53

transformation-related protein 53

tumor protein 53

tumor supressor p53

Conserved Domains (3) summary

pfam00870
Location:95 → 289

P53; P53 DNA-binding domain

pfam07710
Location:319 → 358

P53_tetramer; P53 tetramerisation motif

pfam08563
Location:5 → 28

P53_TAD; P53 transactivation motif

(Vaikuttaa olevan kaksi FYVE- jaksoa)

Peptide sequence and history https://www.ncbi.nlm.nih.gov/protein/NP_000537.3 ORIGIN

        1 meepqsdpsv epplsqetfs dlwkllpenn vlsplpsqam ddlmlspddi eqwftedpgp
       61 deaprmpeaa ppvapapaap tpaapapaps wplsssvpsq ktyqgsygfr lgflhsgtak
      121 svtctyspal nkmfcqlakt cpvqlwvdst pppgtrvram aiykqsqhmt evvrrcphhe
      181 rcsdsdglap pqhlirvegn lrveylddrn tfrhsvvvpy eppevgsdct tihynymcns
      241 scmggmnrrp iltiitleds sgnllgrnsf evrvcacpgr drrteeenlr kkgephhelp
      301 pgstkralpn ntssspqpkk kpldgeyftl qirgrerfem frelnealel kdaqagkepg
      361 gsrahsshlk skkgqstsrh kklmfktegp dsd

Kiinnostava FYVE-domeeni_ mitä siitä tiedetään? Harmaan aivosolun EEA1 reseptoriproteiini omaa myös FYVE domaanin

Kerään jotain lähdetietoa.
https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/fyve-domain 
SITEERAAN tästä linkistä seuraavia  tietoja.

 Löytö on tuo EEA1, joka on tärkeä harmaassa aivokuoressa excitatorisen aminohapon glutamaatin järjestelmässä  toimiva reseptori.  Myös koko  fosfoinositidien ja inositolifosfaattien  PI-aineenvaihdunta-alue on aivoissa tärkeä.  Siihen järjestelmäänkin kuuluu inositolijohdannaisia kai  yli 35 erilaista.  kehon  tapa hyödyntää  FYVE-domeenia on proteiinien tapa seuloa  esiin ja  integroida  PI(3)P  muista  kymmenistä   inositolifosfateista ja  fosfoinositideistä  erilleen. Samoin on  neuroneille  tärkeä saada kehkeytettyä endogeenistä yksittäistä glutamiinihappoa (Glu9  ja pitää yllä sen integroitua aineenvaihduntaa, johon taas on  monta erilaista reseptoria  erottamassa  vaikutusteitä.
 (Lisäksi FYVE- domeenin N-terminaalissa omaa TP53  (Kr.17p13.1) . Otan sen rakenteen erikseen EAA1:n jälkeen )

FYVE domain

The FYVE domain is the only phosphoinositide-binding domain found so far to only bind a single phosphoinositide (namely, PtdIns3P) (De Matteis & Godi, 2004).

From: Methods in Enzymology, 2014

Volume 2

Roger L. Williams, in Handbook of Cell Signaling (Second Edition), 2010

FYVE Domains

The FYVE domains are found in many proteins involved in membrane transport [33].

The FYVE domains from Vps27 [34], Hrs [35], and EEA1 [36,37] consist of two small β-sheets stabilized by two Zn²⁺ ions and a C-terminal α-helix.

The PtdIns(3)P forms hydrogen bonds with the protein by using the 1- and 3-phosphates and the 4-, 5-, and 6-OH groups [37]. The close approach of these hydrogen-bonding partners precludes polyphosphorylated phosphoinositides from binding (Figure 135.3).

 The 3-phosphate forms a hydrogen bond with the last arginine in the (R/K) (R/K)HHCR signature motif characteristic of the FYVE domains. The 1-phosphate interacts with the protein via the first Arg of this motif. Like the PH domains, the FYVE domain buries only one face of the bound phosphoinositide.

 For EEA1, the face with the axial 2-OH is exposed to solution. The presence of the coiled-coil region preceding the EEA1 FYVE domain helps to unambiguously define the mode of membrane interaction and suggests that a loop flanking the PtdIns(3)P pocket, the “turret” loop, penetrates into the lipid bilayer (Figure 135.3). Biophysical measurements indicate that this partial membrane penetration follows rather than precedes specific PtdIns(3)P binding [38].

• LISÄTIETO PubMed Gene EEA1 

 EAA1 gene, (Kr.11q23.3), KA1, GRIK, GluK4

Preferred Names

glutamate receptor ionotropic, kainate 4

Names

excitatory amino acid receptor 1

glutamate receptor KA1

glutamate receptor, ionotropic, kainate 4

Conserved Domains (4) summary

cd06394
Location:26 → 400

PBP1_iGluR_Kainate_KA1_2; N-terminal leucine/isoleucine/valine-binding protein (LIVBP)-like domain of the KA1 and KA2 subunits of Kainate receptor

cd13724
Location:415 → 785

PBP2_iGluR_kainate_KA1; The ligand-binding domain of the kainate subtype KA1 of ionotropic glutamate receptors, a member of the type 2 periplasmic-binding fold protein superfamily

pfam00060
Location:547 → 816

Lig_chan; Ligand-gated ion channel

pfam01094
Location:43 → 382

ANF_receptor; Receptor family ligand binding region

 FYVE- ei ole merkitty konservoituneisiin domaaneihin mutta näkee tuosta peptidirakenteesta jotain, asetan tummalla FYVE jaksoja  muutaman pätkän sekvenssitä. niitä on kai enemmän kuin kaksi, itseasiassa N-terminaalista  päin  on paljon FYVE- jaksoja.  C-terminaali on toista  sorttia. Tietysti vasta käytännöstä näkee, mikä  FYVE jakso kiinnittää PI3P.  Tiedemiehet eivät ole kirjoitaneet tähän, minkä jakson he kutsuvat FYVE-domeeniksi, poimin vain jaksot jossa on  yksittäinen F Y V E järjestys havaittavissa.

https://www.ncbi.nlm.nih.gov/protein/NP_001269399.1

ORIGIN      
        1 mprvsaplvl lpawlvmvac sphslriaai lddpmecsrg erlsitlakn rinraperlg
       61 kakvevdife llrdseyeta etmcqilpkg vvavlgpsss passsiisni cgekevphfk
      121 vapeefvkfq fqrfttlnlh psntdisvav agilnffnct taclicakae cllnlekllr
      181 qfliskdtls vrmlddtrdp tpllkeirdd ktatiiihan asmshtillk aaelgmvsay
      241 ytyiftnlef slqrmdslvd drvnilgfsi fnqshaffqe faqslnqswq encdhvpftg
      301 palssallfd avyavvtavq elnrsqeigv kplscgsaqi wqhgtslmny lrmveleglt
      361 ghiefnskgq rsnyalkilq ftrngfrqig qwhvaeglsm dshlyasnis dtlfnttlvv
      421 ttilenpylm lkgnhqemeg ndryegfcvd mlkelaeilr fnykirlvgd gvygvpeang
      481 twtgmvgeli arkadlavag ltitaerekv idfskpfmtl gisilyrvhm grkpgyfsfl
      541 dpfspgvwlf mllaylavsc vlflvarltp yewysphpca qgrcnllvnq yslgnslwfp
      601 vggfmqqgst iapralstrc vsgvwwaftl iiissytanl aafltvqrmd vpiesvddla
      661 dqtaieygti hggssmtffq nsryqtyqrm wnymyskqps vfvksteegi arvlnsnyaf
      721 llestmneyy rqrncnltqi gglldtkgyg igmpvgsvfr defdlailql qennrleilk
      781 rkwweggkcp keedhrakgl gmeniggifv vlicglivai fmamleflwt lrhseatevs
      841 vcqemvtelr siilcqdsih prrrraavpp prppipeerr prgtatlsng klcgagepdq
      901 laqrlaqeaa lvargcthir vcpecrrfqg lrarpspars eeslewektt nssepe

VPS15 (Kr.3q22.1) PIK3R4, p150 , (VPS-associated ESCRT-0)

PI3P synteesi , VPS 15 ja VPS34 , mitä ne tekevät vakuolaaristen proteiinien lajitelujärjstlmään assosioituneina?

Vacuolar Protein Sorting Associated protein 15

VPS15 (Kr. 3q22.3), PIK3R4, Phosphoinositide-3-kinase regulatory subunit 4.

Also known as p150; VPS15

Expression Ubiquitous expression in thyroid (RPKM 9.2), testis (RPKM 8.7) and 25 other tissues See moreOrthologs mouse all

Preferred Names

phosphoinositide 3-kinase regulatory subunit 4

Names

PI3-kinase p150 subunit

PI3-kinase regulatory subunit 4

phosphatidylinositol 3-kinase-associated p150

phosphoinositide 3-kinase adaptor protein

phosphoinositide-3-kinase, regulatory subunit 4, p150

NP_055417.1

• EC 2.7.11.1

Peptidirakenne:

Conserved Domains (8) summary

smart00320
Location:1327 → 1358

WD40; WD40 repeats

smart00220
Location:26 → 309

S_TKc; Serine/Threonine protein kinases, catalytic domain

COG2319
Location:991 → 1358

WD40; WD40 repeat [General function prediction only]

cd13980
Location:25 → 320

STKc_Vps15; Catalytic domain of the Serine/Threonine kinase, Vacuolar protein sorting-associated protein 15

pfam07539
Location:352 → 448

DRIM; Down-regulated in metastasis

sd00044
Location:539 → 566

HEAT; HEAT repeat [structural motif]

sd00039
Location:997 → 1040

7WD40; WD40 repeat [structural motif]

cl02567
Location:985 → 1269

WD40; WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from ...

Related articles in PubMed

1. Autophagy dysregulation in Danon disease. Nascimbeni AC, et al. Cell Death Dis, 2017 Jan 19. PMID 28102838, Free PMC Article
2. High expression of PI3K core complex genes is associated with poor prognosis in chronic lymphocytic leukemia. Kristensen L, et al. Leuk Res, 2015 Jun. PMID 25840748
3. hVps15, but not Ca2+/CaM, is required for the activity and regulation of hVps34 in mammalian cells. Yan Y, et al. Biochem J, 2009 Feb 1. PMID 18957027, Free PMC Article
4. The microtubule plus-end proteins EB1 and dynactin have differential effects on microtubule polymerization. Ligon LA, et al. Mol Biol Cell, 2003 Apr. PMID 12686597, Free PMC Article
5. Signal transduction pathways mediated by the interaction of CpG DNA with Toll-like receptor 9. Takeshita F, et al. Semin Immunol, 2004 Feb. PMID 14751759
   

See all (37) citations in PubMed
See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. Both Danon Disease and glycogen storage disease type II show accumulation and altered localization of VPS15 in autophagy-incompetent fibers. However, TFEB displays a different pattern between these two lysosomal storage diseases
2. High expression of PI3K core complex genes is associated with poor prognosis in chronic lymphocytic leukemia.
3. A specific sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates both receptor degradation and cytokinesis, whereas ATG14L, a PI3K-III subunit involved in autophagy, is not required.
4. hVps15, but not Ca2+/CaM, is required for the activity and regulation of hVps34 in mammalian cells
   

Rakenne ja historia

phosphoinositide 3-kinase regulatory subunit 4 [Homo sapiens]

NCBI Reference Sequence: NP_055417.1
Identical Proteins FASTA Graphics

Go to:

LOCUS       NP_055417               1358 aa            linear   PRI 01-APR-2018
DEFINITION  phosphoinositide 3-kinase regulatory subunit 4 [Homo sapiens].
ACCESSION   NP_055417
VERSION     NP_055417.1
DBSOURCE    REFSEQ: accession NM_014602.2
KEYWORDS    RefSeq.
SOURCE      Homo sapiens (human)
  ORGANISM  Homo sapiens
            Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
            Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
            Catarrhini; Hominidae; Homo.
REFERENCE   1  (residues 1 to 1358)
  AUTHORS   Nascimbeni AC, Fanin M, Angelini C and Sandri M.
  TITLE     Autophagy dysregulation in Danon disease
  JOURNAL   Cell Death Dis 8 (1), e2565 (2017)
   PUBMED   28102838
  REMARK    GeneRIF: Both Danon Disease and glycogen storage disease type II
            show accumulation and altered localization of VPS15 in
            autophagy-incompetent fibers. However, TFEB displays a different
            pattern between these two lysosomal storage diseases
            Publication Status: Online-Only
REFERENCE   2  (residues 1 to 1358)
  AUTHORS   Kristensen L, Kristensen T, Abildgaard N, Thomassen M, Frederiksen
            M, Mour
phosphoinositide 3-kinase regulatory subunit 4 [Homo sapiens]

NCBI Reference Sequence: NP_055417.1

Identical Proteins FASTA Graphics
Go to:

LOCUS       NP_055417               1358 aa            linear   PRI 01-APR-2018
DEFINITION  phosphoinositide 3-kinase regulatory subunit 4 [Homo sapiens].
ACCESSION   NP_055417
VERSION     NP_055417.1
DBSOURCE    REFSEQ: accession NM_014602.2
KEYWORDS    RefSeq.
SOURCE      Homo sapiens (human)
  ORGANISM  Homo sapiens
            Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
            Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
            Catarrhini; Hominidae; Homo.
REFERENCE   1  (residues 1 to 1358)
  AUTHORS   Nascimbeni AC, Fanin M, Angelini C and Sandri M.
  TITLE     Autophagy dysregulation in Danon disease
  JOURNAL   Cell Death Dis 8 (1), e2565 (2017)
   PUBMED   28102838
  REMARK    GeneRIF: Both Danon Disease and glycogen storage disease type II
            show accumulation and altered localization of VPS15 in
            autophagy-incompetent fibers. However, TFEB displays a different
            pattern between these two lysosomal storage diseases
            Publication Status: Online-Only
REFERENCE   2  (residues 1 to 1358)
  AUTHORS   Kristensen L, Kristensen T, Abildgaard N, Thomassen M, Frederiksen
            M, Mourits-Andersen T and Moller MB.
  TITLE     High expression of PI3K core complex genes is associated with poor
            prognosis in chronic lymphocytic leukemia
  JOURNAL   Leuk. Res. 39 (6), 555-560 (2015)
   PUBMED   25840748
  REMARK    GeneRIF: High expression of PI3K core complex genes is associated
            with poor prognosis in chronic lymphocytic leukemia.
REFERENCE   3  (residues 1 to 1358)
  AUTHORS   Cao Y, Wang Y, Abi Saab WF, Yang F, Pessin JE and Backer JM.
  TITLE     NRBF2 regulates macroautophagy as a component of Vps34 Complex I
  JOURNAL   Biochem. J. 461 (2), 315-322 (2014)
   PUBMED   24785657
REFERENCE   4  (residues 1 to 1358)
  AUTHORS   Lu J, He L, Behrends C, Araki M, Araki K, Jun Wang Q, Catanzaro JM,
            Friedman SL, Zong WX, Fiel MI, Li M and Yue Z.
  TITLE     NRBF2 regulates autophagy and prevents liver injury by modulating
            Atg14L-linked phosphatidylinositol-3 kinase III activity
  JOURNAL   Nat Commun 5, 3920 (2014)
   PUBMED   24849286
  REMARK    Publication Status: Online-Only
REFERENCE   5  (residues 1 to 1358)
  AUTHORS   Fogel AI, Dlouhy BJ, Wang C, Ryu SW, Neutzner A, Hasson SA, Sideris
            DP, Abeliovich H and Youle RJ.
  TITLE     Role of membrane association and Atg14-dependent phosphorylation in
            beclin-1-mediated autophagy
  JOURNAL   Mol. Cell. Biol. 33 (18), 3675-3688 (2013)
   PUBMED   23878393
REFERENCE   6  (residues 1 to 1358)
  AUTHORS   Stein MP, Feng Y, Cooper KL, Welford AM and Wandinger-Ness A.
  TITLE     Human VPS34 and p150 are Rab7 interacting partners
  JOURNAL   Traffic 4 (11), 754-771 (2003)
   PUBMED   14617358
REFERENCE   7  (residues 1 to 1358)
  AUTHORS   Ligon LA, Shelly SS, Tokito M and Holzbaur EL.
  TITLE     The microtubule plus-end proteins EB1 and dynactin have
            differential effects on microtubule polymerization
  JOURNAL   Mol. Biol. Cell 14 (4), 1405-1417 (2003)
   PUBMED   12686597
REFERENCE   8  (residues 1 to 1358)
  AUTHORS   Koyasu S.
  TITLE     The role of PI3K in immune cells
  JOURNAL   Nat. Immunol. 4 (4), 313-319 (2003)
   PUBMED   12660731
  REMARK    Review article
REFERENCE   9  (residues 1 to 1358)
  AUTHORS   Askham JM, Vaughan KT, Goodson HV and Morrison EE.
  TITLE     Evidence that an interaction between EB1 and p150(Glued) is
            required for the formation and maintenance of a radial microtubule
            array anchored at the centrosome
  JOURNAL   Mol. Biol. Cell 13 (10), 3627-3645 (2002)
   PUBMED   12388762
REFERENCE   10 (residues 1 to 1358)
  AUTHORS   Panaretou C, Domin J, Cockcroft S and Waterfield MD.
  TITLE     Characterization of p150, an adaptor protein for the human
            phosphatidylinositol (PtdIns) 3-kinase. Substrate presentation by
            phosphatidylinositol transfer protein to the p150.Ptdins 3-kinase
            complex
  JOURNAL   J. Biol. Chem. 272 (4), 2477-2485 (1997)
   PUBMED   8999962
COMMENT     VALIDATED REFSEQ: This record has undergone validation or
            preliminary review. The reference sequence was derived from
            BP359657.1 and Y08991.1.
            
            Publication Note:  This RefSeq record includes a subset of the
            publications that are available for this gene. Please see the Gene
            record to access additional publications.
            
            ##Evidence-Data-START##
            Transcript exon combination :: Y08991.1, SRR1803616.271117.1
                                           [ECO:0000332]
            RNAseq introns              :: mixed/partial sample support
                                           SAMEA1965299, SAMEA1966682
                                           [ECO:0000350]
            ##Evidence-Data-END##
FEATURES             Location/Qualifiers
     source          1..1358
                     /organism="Homo sapiens"
                     /db_xref="taxon:9606"
                     /chromosome="3"
                     /map="3q22.1"
     Protein         1..1358
                     /product="phosphoinositide 3-kinase regulatory subunit 4"
                     /EC_number="2.7.11.1"
                     /note="phosphatidylinositol 3-kinase-associated p150;
                     phosphoinositide-3-kinase, regulatory subunit 4, p150;
                     PI3-kinase regulatory subunit 4; PI3-kinase p150 subunit;
                     phosphoinositide 3-kinase adaptor protein"
                     /calculated_mol_wt=152973
     Region          25..320
                     /region_name="STKc_Vps15"
                     /note="Catalytic domain of the Serine/Threonine kinase,
                     Vacuolar protein sorting-associated protein 15; cd13980"
                     /db_xref="CDD:270882"
     Region          26..309
                     /region_name="S_TKc"
                     /note="Serine/Threonine protein kinases, catalytic domain;
                     smart00220"
                     /db_xref="CDD:214567"
     Site            order(32..36,40,51,53,85,103..106,109,111,148,150,
                     152..153,155,166,169,192..195)
                     /site_type="active"
                     /db_xref="CDD:270882"
     Site            order(32..36,40,51,53,85,103..106,109,148,150,152..153,
                     155,166)
                     /site_type="other"
                     /note="ATP binding site [chemical binding]"
                     /db_xref="CDD:270882"
     Site            order(36,109,111,148,150,152,169,192..195)
                     /site_type="other"
                     /note="polypeptide substrate binding site [polypeptide
                     binding]"
                     /db_xref="CDD:270882"
     Site            order(165..187,192..195)
                     /site_type="other"
                     /note="activation loop (A-loop)"
                     /db_xref="CDD:270882"
     Region          <352 ..="">448
                     /region_name="DRIM"
                     /note="Down-regulated in metastasis; pfam07539"
                     /db_xref="CDD:284870"
     Region          377..408
                     /region_name="HEAT repeat"
                     /note="HEAT repeat [structural motif]"
                     /db_xref="CDD:293787"
     Region          413..450
                     /region_name="HEAT 1"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)"
     Region          417..443
                     /region_name="HEAT repeat"
                     /note="HEAT repeat [structural motif]"
                     /db_xref="CDD:293787"
     Region          458..495
                     /region_name="HEAT 2"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)"
     Region          460..489
                     /region_name="HEAT repeat"
                     /note="HEAT repeat [structural motif]"
                     /db_xref="CDD:293787"
     Region          539..566
                     /region_name="HEAT repeat"
                     /note="HEAT repeat [structural motif]"
                     /db_xref="CDD:293787"
     Site            order(554..555,558,562..563,566,595..596,599,602..603,606,
                     633..634,637,640..641,673..674,677,680..681)
                     /site_type="other"
                     /note="putative peptide binding site [polypeptide
                     binding]"
                     /db_xref="CDD:293787"
     Region          572..610
                     /region_name="HEAT 3"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)"
     Region          576..607
                     /region_name="HEAT repeat"
                     /note="HEAT repeat [structural motif]"
                     /db_xref="CDD:293787"
     Region          614..641
                     /region_name="HEAT repeat"
                     /note="HEAT repeat [structural motif]"
                     /db_xref="CDD:293787"
     Region          652..682
                     /region_name="HEAT repeat"
                     /note="HEAT repeat [structural motif]"
                     /db_xref="CDD:293787"
     Site            808
                     /site_type="phosphorylation"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="Phosphoserine. {ECO:0000244|PubMed:19369195};
                     propagated from UniProtKB/Swiss-Prot (Q99570.3)"
     Site            813
                     /site_type="phosphorylation"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="Phosphoserine. {ECO:0000244|PubMed:23186163};
                     propagated from UniProtKB/Swiss-Prot (Q99570.3)"
     Site            853
                     /site_type="phosphorylation"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="Phosphoserine. {ECO:0000244|PubMed:19369195};
                     propagated from UniProtKB/Swiss-Prot (Q99570.3)"
     Site            865
                     /site_type="phosphorylation"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="Phosphoserine. {ECO:0000244|PubMed:19369195};
                     propagated from UniProtKB/Swiss-Prot (Q99570.3)"
     Region          985..1269
                     /region_name="WD40"
                     /note="WD40 domain, found in a number of eukaryotic
                     proteins that cover a wide variety of functions including
                     adaptor/regulatory modules in signal transduction,
                     pre-mRNA processing and cytoskeleton assembly; typically
                     contains a GH dipeptide 11-24 residues from...; cl02567"
                     /db_xref="CDD:295369"
     Region          991..1358
                     /region_name="WD40"
                     /note="WD40 repeat [General function prediction only];
                     COG2319"
                     /db_xref="CDD:225201"
     Region          991..1030
                     /region_name="WD 1"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)"
     Site            order(992,1010,1014,1020..1021,1039..1040,1059,1063,
                     1069..1070,1090..1091,1104,1113,1118,1124..1125,1137,1158,
                     1162,1168..1169,1182..1183,1201,1206,1213..1214,
                     1226..1227,1258,1262,1268..1269)
                     /site_type="other"
                     /note="structural tetrad"
                     /db_xref="CDD:238121"
     Region          997..1040
                     /region_name="WD40 repeat"
                     /note="WD40 repeat [structural motif]"
                     /db_xref="CDD:293791"
     Region          1040..1079
                     /region_name="WD 2"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)"
     Region          1045..1091
                     /region_name="WD40 repeat"
                     /note="WD40 repeat [structural motif]"
                     /db_xref="CDD:293791"
     Region          1093..1134
                     /region_name="WD 3"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)"
     Region          1099..1136
                     /region_name="WD40 repeat"
                     /note="WD40 repeat [structural motif]"
                     /db_xref="CDD:293791"
     Region          1139..1178
                     /region_name="WD 4"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)"
     Region          1144..1179
                     /region_name="WD40 repeat"
                     /note="WD40 repeat [structural motif]"
                     /db_xref="CDD:293791"
     Region          1182..1223
                     /region_name="WD 5"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)"
     Region          1187..1236
                     /region_name="WD40 repeat"
                     /note="WD40 repeat [structural motif]"
                     /db_xref="CDD:293791"
     Region          1237..1278
                     /region_name="WD 6"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)"
     Region          1242..1268
                     /region_name="WD40 repeat"
                     /note="WD40 repeat [structural motif]"
                     /db_xref="CDD:293791"
     Site            1316
                     /site_type="phosphorylation"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="Phosphothreonine. {ECO:0000244|PubMed:18691976};
                     propagated from UniProtKB/Swiss-Prot (Q99570.3)"
     Region          1327..1358
                     /region_name="WD 7"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)"
     Region          <1327 ..1358="" 1..1358="" 1021="" 1081="" 1141="" 1201="" 121="" 1261="" 1321="" 1332..1357="" 181="" 1="" 241="" 301="" 361="" 39="" 421="" 481="" 541="" 555-560="" 601="" 61="" 661="" 721="" 781="" 841="" 901="" 961="" a="" adfnyffdts="" akqmmenaew="" and="" apflchpnlw="" aqddativrl="" aqnclpfqka="" arakhreglv="" associated="" ayaenialla="" aypersyvva="" cds="" chronic="" cmcqlgllqk="" coded_by="NM_014602.2:582..4658" complex="" core="" cqgshylaia="" csndgtvkiw="" db_xref="MIM:602610" ddkrarkhvk="" dgivkvwk="" dgnpilltag="" dlpekaegep="" dqkedgcvvd="" eeeedkllal="" ehksavnrir="" eleymrdpst="" erilvirkdl="" erklvllsvl="" eskppppgwr="" etalrflelv="" expression="" eyilpgiahl="" faketflsad="" gene="PIK3R4" gene_synonym="p150; VPS15" genes="" gniihnlcgh="" gpsddtprrg="" gstsspsvsy="" hdssqkgvid="" hffpeqvlnk="" high="" hpngnydtel="" hpsrarirrl="" href="https://www.ncbi.nlm.nih.gov/pubmed/25840748" iaavqgnnev="" ieasklpksp="" iedhsirelv="" ifsagcviae="" iggrvktltf="" ihqcwlcigt="" iitdvatfqt="" in="" ipvlsstilp="" irygavgfit="" is="" itrlcvffgr="" its-andersen="" ivgvaayvgw="" ivkqtlmeng="" journal="" kanivdqshl="" kdfmmksnka="" kenglvilvs="" kepvsrsifd="" kihplqsril="" kptylpednp="" kreqcnaeri="" krngslpdcp="" ksgvrhgdik="" ktelqqliqq="" laalgitgrq="" leelkirlns="" leuk.="" leukemia="" lfrhlhmrqk="" lfrqyvrdnl="" lftegvplfd="" lilhlaprls="" lkkllsqgmt="" lsqllayrng="" ltkvlalvke="" lvgwdlrsss="" lymphocytic="" mb.="" mgnqlagiap="" mhhfnsgaqs="" mitflndknd="" moller="" mpqalpkgsd="" nawtlkhdlk="" nniekrwiaf="" note="WD40 repeat [structural motif]" nsqkmegktt="" of="" origin="" peslpvghhd="" phvyefasdi="" pi3k="" pkgllvahlh="" plselqpsph="" plstssqvpe="" plvdlnsnqr="" pnneeidevt="" poor="" ppedpaiaql="" prognosis="" prvraealrt="" pubmed="" pyitqpiiqi="" qalhemvqqk="" qdsnvneewk="" qeviqtgkpp="" qiltavdqah="" qkandvllsh="" qlknlnmend="" qqglsdaeef="" qrgnafpeif="" qsssilkpll="" region="" region_name="WD40 repeat" res.="" rfqlpisshc="" rftlwassap="" rfvdggmfat="" rleaedylkq="" rrrtcyiape="" rsessagicv="" sdihdfeydk="" sdmkirfwdl="" sdngavqllg="" sekasekaam="" sglitsfavd="" slgstrffkv="" smfgsldppn="" smhplyqswv="" smwdmetgdr="" sqilsvesyf="" ssgtmacwdm="" styqirittc="" svhgiycspa="" t="" tenvmvtswn="" title="" tlpltsykqe="" tqgfivtasr="" tqmihrepdk="" trgelkramd="" ttrsiltysr="" vdlvktkqep="" veilldritp="" vitsclqtlk="" vivkalyalt="" vlayatvngs="" vprndiniyp="" vqeiqnkqkv="" vsdehslfat="" vttvqnkkpv="" vvarqistad="" vvkvfaiqdp="" vvtllsdpen="" vycklmpyld="" whlrgaffds="" with="" wvlltdfasf="" yalrskdits="" ycdsklaale="" ydristrpfl="" yllhfsndsv="" yrkiiegtev="" ytflqpymaq="">25840748

REMARK GeneRIF: High expression of PI3K core complex genes is associated with poor prognosis in chronic lymphocytic leukemia. REFERENCE 3 (residues 1 to 1358) AUTHORS Cao Y, Wang Y, Abi Saab WF, Yang F, Pessin JE and Backer JM. TITLE NRBF2 regulates macroautophagy as a component of Vps34 Complex I JOURNAL Biochem. J. 461 (2), 315-322 (2014) PUBMED 24785657 REFERENCE 4 (residues 1 to 1358) AUTHORS Lu J, He L, Behrends C, Araki M, Araki K, Jun Wang Q, Catanzaro JM, Friedman SL, Zong WX, Fiel MI, Li M and Yue Z. TITLE NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity JOURNAL Nat Commun 5, 3920 (2014) PUBMED 24849286 REMARK Publication Status: Online-Only REFERENCE 5 (residues 1 to 1358) AUTHORS Fogel AI, Dlouhy BJ, Wang C, Ryu SW, Neutzner A, Hasson SA, Sideris DP, Abeliovich H and Youle RJ. TITLE Role of membrane association and Atg14-dependent phosphorylation in beclin-1-mediated autophagy JOURNAL Mol. Cell. Biol. 33 (18), 3675-3688 (2013) PUBMED 23878393 REFERENCE 6 (residues 1 to 1358) AUTHORS Stein MP, Feng Y, Cooper KL, Welford AM and Wandinger-Ness A. TITLE Human VPS34 and p150 are Rab7 interacting partners JOURNAL Traffic 4 (11), 754-771 (2003) PUBMED 14617358 REFERENCE 7 (residues 1 to 1358) AUTHORS Ligon LA, Shelly SS, Tokito M and Holzbaur EL. TITLE The microtubule plus-end proteins EB1 and dynactin have differential effects on microtubule polymerization JOURNAL Mol. Biol. Cell 14 (4), 1405-1417 (2003) PUBMED 12686597 REFERENCE 8 (residues 1 to 1358) AUTHORS Koyasu S. TITLE The role of PI3K in immune cells JOURNAL Nat. Immunol. 4 (4), 313-319 (2003) PUBMED 12660731 REMARK Review article REFERENCE 9 (residues 1 to 1358) AUTHORS Askham JM, Vaughan KT, Goodson HV and Morrison EE. TITLE Evidence that an interaction between EB1 and p150(Glued) is required for the formation and maintenance of a radial microtubule array anchored at the centrosome JOURNAL Mol. Biol. Cell 13 (10), 3627-3645 (2002) PUBMED 12388762 REFERENCE 10 (residues 1 to 1358) AUTHORS Panaretou C, Domin J, Cockcroft S and Waterfield MD. TITLE Characterization of p150, an adaptor protein for the human phosphatidylinositol (PtdIns) 3-kinase. Substrate presentation by phosphatidylinositol transfer protein to the p150.Ptdins 3-kinase complex JOURNAL J. Biol. Chem. 272 (4), 2477-2485 (1997) PUBMED 8999962 COMMENT VALIDATED REFSEQ: This record has undergone validation or preliminary review. The reference sequence was derived from BP359657.1 and Y08991.1. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. ##Evidence-Data-START## Transcript exon combination :: Y08991.1, SRR1803616.271117.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support SAMEA1965299, SAMEA1966682 [ECO:0000350] ##Evidence-Data-END## FEATURES Location/Qualifiers source 1..1358 /organism="Homo sapiens" /db_xref="taxon:9606" /chromosome="3" /map="3q22.1" Protein 1..1358 /product="phosphoinositide 3-kinase regulatory subunit 4" /EC_number="2.7.11.1" /note="phosphatidylinositol 3-kinase-associated p150; phosphoinositide-3-kinase, regulatory subunit 4, p150; PI3-kinase regulatory subunit 4; PI3-kinase p150 subunit; phosphoinositide 3-kinase adaptor protein" /calculated_mol_wt=152973 Region 25..320 /region_name="STKc_Vps15" /note="Catalytic domain of the Serine/Threonine kinase, Vacuolar protein sorting-associated protein 15; cd13980" /db_xref="CDD:270882" Region 26..309 /region_name="S_TKc" /note="Serine/Threonine protein kinases, catalytic domain; smart00220" /db_xref="CDD:214567" Site order(32..36,40,51,53,85,103..106,109,111,148,150, 152..153,155,166,169,192..195) /site_type="active" /db_xref="CDD:270882" Site order(32..36,40,51,53,85,103..106,109,148,150,152..153, 155,166) /site_type="other" /note="ATP binding site [chemical binding]" /db_xref="CDD:270882" Site order(36,109,111,148,150,152,169,192..195) /site_type="other" /note="polypeptide substrate binding site [polypeptide binding]" /db_xref="CDD:270882" Site order(165..187,192..195) /site_type="other" /note="activation loop (A-loop)" /db_xref="CDD:270882" Region <352 ..="">448 /region_name="DRIM" /note="Down-regulated in metastasis; pfam07539" /db_xref="CDD:284870" Region 377..408 /region_name="HEAT repeat" /note="HEAT repeat [structural motif]" /db_xref="CDD:293787" Region 413..450 /region_name="HEAT 1" /experiment="experimental evidence, no additional details recorded" /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)" Region 417..443 /region_name="HEAT repeat" /note="HEAT repeat [structural motif]" /db_xref="CDD:293787" Region 458..495 /region_name="HEAT 2" /experiment="experimental evidence, no additional details recorded" /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)" Region 460..489 /region_name="HEAT repeat" /note="HEAT repeat [structural motif]" /db_xref="CDD:293787" Region 539..566 /region_name="HEAT repeat" /note="HEAT repeat [structural motif]" /db_xref="CDD:293787" Site order(554..555,558,562..563,566,595..596,599,602..603,606, 633..634,637,640..641,673..674,677,680..681) /site_type="other" /note="putative peptide binding site [polypeptide binding]" /db_xref="CDD:293787" Region 572..610 /region_name="HEAT 3" /experiment="experimental evidence, no additional details recorded" /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)" Region 576..607 /region_name="HEAT repeat" /note="HEAT repeat [structural motif]" /db_xref="CDD:293787" Region 614..641 /region_name="HEAT repeat" /note="HEAT repeat [structural motif]" /db_xref="CDD:293787" Region 652..682 /region_name="HEAT repeat" /note="HEAT repeat [structural motif]" /db_xref="CDD:293787" Site 808 /site_type="phosphorylation" /experiment="experimental evidence, no additional details recorded" /note="Phosphoserine. {ECO:0000244|PubMed:19369195}; propagated from UniProtKB/Swiss-Prot (Q99570.3)" Site 813 /site_type="phosphorylation" /experiment="experimental evidence, no additional details recorded" /note="Phosphoserine. {ECO:0000244|PubMed:23186163}; propagated from UniProtKB/Swiss-Prot (Q99570.3)" Site 853 /site_type="phosphorylation" /experiment="experimental evidence, no additional details recorded" /note="Phosphoserine. {ECO:0000244|PubMed:19369195}; propagated from UniProtKB/Swiss-Prot (Q99570.3)" Site 865 /site_type="phosphorylation" /experiment="experimental evidence, no additional details recorded" /note="Phosphoserine. {ECO:0000244|PubMed:19369195}; propagated from UniProtKB/Swiss-Prot (Q99570.3)" Region 985..1269 /region_name="WD40" /note="WD40 domain, found in a number of eukaryotic proteins that cover a wide variety of functions including adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly; typically contains a GH dipeptide 11-24 residues from...; cl02567" /db_xref="CDD:295369" Region 991..1358 /region_name="WD40" /note="WD40 repeat [General function prediction only]; COG2319" /db_xref="CDD:225201" Region 991..1030 /region_name="WD 1" /experiment="experimental evidence, no additional details recorded" /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)" Site order(992,1010,1014,1020..1021,1039..1040,1059,1063, 1069..1070,1090..1091,1104,1113,1118,1124..1125,1137,1158, 1162,1168..1169,1182..1183,1201,1206,1213..1214, 1226..1227,1258,1262,1268..1269) /site_type="other" /note="structural tetrad" /db_xref="CDD:238121" Region 997..1040 /region_name="WD40 repeat" /note="WD40 repeat [structural motif]" /db_xref="CDD:293791" Region 1040..1079 /region_name="WD 2" /experiment="experimental evidence, no additional details recorded" /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)" Region 1045..1091 /region_name="WD40 repeat" /note="WD40 repeat [structural motif]" /db_xref="CDD:293791" Region 1093..1134 /region_name="WD 3" /experiment="experimental evidence, no additional details recorded" /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)" Region 1099..1136 /region_name="WD40 repeat" /note="WD40 repeat [structural motif]" /db_xref="CDD:293791" Region 1139..1178 /region_name="WD 4" /experiment="experimental evidence, no additional details recorded" /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)" Region 1144..1179 /region_name="WD40 repeat" /note="WD40 repeat [structural motif]" /db_xref="CDD:293791" Region 1182..1223 /region_name="WD 5" /experiment="experimental evidence, no additional details recorded" /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)" Region 1187..1236 /region_name="WD40 repeat" /note="WD40 repeat [structural motif]" /db_xref="CDD:293791" Region 1237..1278 /region_name="WD 6" /experiment="experimental evidence, no additional details recorded" /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)" Region 1242..1268 /region_name="WD40 repeat" /note="WD40 repeat [structural motif]" /db_xref="CDD:293791" Site 1316 /site_type="phosphorylation" /experiment="experimental evidence, no additional details recorded" /note="Phosphothreonine. {ECO:0000244|PubMed:18691976}; propagated from UniProtKB/Swiss-Prot (Q99570.3)" Region 1327..1358 /region_name="WD 7" /experiment="experimental evidence, no additional details recorded" /note="propagated from UniProtKB/Swiss-Prot (Q99570.3)" Region <1327 ..1358="" cdd="" cddsrv.cgi="" db_xref="CDD:<a href=" https:="" note="WD40 repeats; smart00320" region_name="WD40" tructure="" uid="197651" www.ncbi.nlm.nih.gov="">197651" Region 1332..1357 /region_name="WD40 repeat" /note="WD40 repeat [structural motif]" /db_xref="CDD:293791" CDS 1..1358 /gene="PIK3R4" /gene_synonym="p150; VPS15" /coded_by="NM_014602.2:582..4658" /db_xref="CCDS:CCDS3067.1" /db_xref="GeneID:30849" /db_xref="HGNC:HGNC:8982" /db_xref="MIM:602610" ORIGIN 1 mgnqlagiap sqilsvesyf sdihdfeydk slgstrffkv arakhreglv vvkvfaiqdp 61 tlpltsykqe leelkirlns aqnclpfqka sekasekaam lfrqyvrdnl ydristrpfl 121 nniekrwiaf qiltavdqah ksgvrhgdik tenvmvtswn wvlltdfasf kptylpednp 181 adfnyffdts rrrtcyiape rfvdggmfat eleymrdpst plvdlnsnqr trgelkramd 241 ifsagcviae lftegvplfd lsqllayrng hffpeqvlnk iedhsirelv tqmihrepdk 301 rleaedylkq qrgnafpeif ytflqpymaq faketflsad erilvirkdl gniihnlcgh 361 dlpekaegep kenglvilvs vitsclqtlk ycdsklaale lilhlaprls veilldritp 421 yllhfsndsv prvraealrt ltkvlalvke vprndiniyp eyilpgiahl aqddativrl 481 ayaenialla etalrflelv qlknlnmend pnneeidevt hpngnydtel qalhemvqqk 541 vvtllsdpen ivkqtlmeng itrlcvffgr qkandvllsh mitflndknd whlrgaffds 601 ivgvaayvgw qsssilkpll qqglsdaeef vivkalyalt cmcqlgllqk phvyefasdi 661 apflchpnlw irygavgfit vvarqistad vycklmpyld pyitqpiiqi erklvllsvl 721 kepvsrsifd yalrskdits lfrhlhmrqk krngslpdcp ppedpaiaql lkkllsqgmt 781 eeeedkllal kdfmmksnka kanivdqshl hdssqkgvid laalgitgrq vdlvktkqep 841 ddkrarkhvk qdsnvneewk smfgsldppn mpqalpkgsd qeviqtgkpp rsessagicv 901 plstssqvpe vttvqnkkpv ipvlsstilp styqirittc ktelqqliqq kreqcnaeri 961 akqmmenaew eskppppgwr pkgllvahlh ehksavnrir vsdehslfat csndgtvkiw 1021 nsqkmegktt ttrsiltysr iggrvktltf cqgshylaia sdngavqllg ieasklpksp 1081 kihplqsril dqkedgcvvd mhhfnsgaqs vlayatvngs lvgwdlrsss nawtlkhdlk 1141 sglitsfavd ihqcwlcigt ssgtmacwdm rfqlpisshc hpsrarirrl smhplyqswv 1201 iaavqgnnev smwdmetgdr rftlwassap plselqpsph svhgiycspa dgnpilltag 1261 sdmkirfwdl aypersyvva gstsspsvsy yrkiiegtev vqeiqnkqkv gpsddtprrg 1321 peslpvghhd iitdvatfqt tqgfivtasr dgivkvwk //