FIG4_MOUSE
ID FIG4_MOUSE Reviewed; 907 AA.
AC Q91WF7; Q6A092;
DT 05-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 127.
DE RecName: Full=Polyphosphoinositide phosphatase;
DE EC=3.1.3.- {ECO:0000250|UniProtKB:Q92562};
DE EC=3.1.3.36 {ECO:0000250|UniProtKB:Q92562};
DE EC=3.1.3.86 {ECO:0000250|UniProtKB:Q92562};
DE AltName: Full=Phosphatidylinositol 3,5-bisphosphate 5-phosphatase;
DE AltName: Full=SAC domain-containing protein 3;
DE AltName: Full=Serine-protein phosphatase FIG4;
DE EC=3.1.3.16 {ECO:0000250|UniProtKB:Q92562};
GN Name=Fig4; Synonyms=Kiaa0274, Sac3;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J, and FVB/N; TISSUE=Kidney, and Retina;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 256-907.
RC TISSUE=Natural killer cell;
RX PubMed=15368895; DOI=10.1093/dnares/11.3.205;
RA Okazaki N., Kikuno R., Ohara R., Inamoto S., Koseki H., Hiraoka S.,
RA Saga Y., Seino S., Nishimura M., Kaisho T., Hoshino K., Kitamura H.,
RA Nagase T., Ohara O., Koga H.;
RT "Prediction of the coding sequences of mouse homologues of KIAA gene: IV.
RT The complete nucleotide sequences of 500 mouse KIAA-homologous cDNAs
RT identified by screening of terminal sequences of cDNA clones randomly
RT sampled from size-fractionated libraries.";
RL DNA Res. 11:205-218(2004).
RN [3]
RP FUNCTION, TISSUE SPECIFICITY, AND DISEASE.
RX PubMed=17572665; DOI=10.1038/nature05876;
RA Chow C.Y., Zhang Y., Dowling J.J., Jin N., Adamska M., Shiga K.,
RA Szigeti K., Shy M.E., Li J., Zhang X., Lupski J.R., Weisman L.S.,
RA Meisler M.H.;
RT "Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and
RT patients with CMT4J.";
RL Nature 448:68-72(2007).
RN [4]
RP IDENTIFICATION IN THE PI(3,5)P2 REGULATORY COMPLEX, FUNCTION, AND
RP SUBCELLULAR LOCATION.
RX PubMed=19037259; DOI=10.1038/emboj.2008.248;
RA Jin N., Chow C.Y., Liu L., Zolov S.N., Bronson R., Davisson M.,
RA Petersen J.L., Zhang Y., Park S., Duex J.E., Goldowitz D., Meisler M.H.,
RA Weisman L.S.;
RT "VAC14 nucleates a protein complex essential for the acute interconversion
RT of PI3P and PI(3,5)P(2) in yeast and mouse.";
RL EMBO J. 27:3221-3234(2008).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: The PI(3,5)P2 regulatory complex regulates both the synthesis
CC and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2).
CC In vitro, hydrolyzes all three D5-phosphorylated polyphosphoinositide
CC substrates in the order PtdIns(4,5)P2 > PtdIns(3,5)P2 >
CC PtdIns(3,4,5)P3. Plays a role in the biogenesis of endosome carrier
CC vesicles (ECV) / multivesicular bodies (MVB) transport intermediates
CC from early endosomes. {ECO:0000269|PubMed:17572665,
CC ECO:0000269|PubMed:19037259}.
CC -!- FUNCTION: Dual specificity phosphatase component of the PI(3,5)P2
CC regulatory complex which regulates both the synthesis and turnover of
CC phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). Catalyzes the
CC dephosphorylation of phosphatidylinositol 3,5-bisphosphate
CC (PtdIns(3,5)P2) to form phosphatidylinositol 3-phosphate. Has serine-
CC protein phosphatase activity acting on PIKfyve to stimulate its lipid
CC kinase activity, its catalytically activity being required for maximal
CC PI(3,5)P2 production. In vitro, hydrolyzes all three D5-phosphorylated
CC polyphosphoinositide and although displaying preferences for
CC PtdIns(3,5)P2, it is capable of hydrolyzing PtdIns(3,4,5)P3 and
CC PtdIns(4,5)P2, at least in vitro. {ECO:0000250|UniProtKB:Q92562,
CC ECO:0000269|PubMed:17572665, ECO:0000269|PubMed:19037259}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-
CC bisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-
CC inositol-3-phosphate) + phosphate; Xref=Rhea:RHEA:32955,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:57923,
CC ChEBI:CHEBI:58088; Evidence={ECO:0000250|UniProtKB:Q92562};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:32956;
CC Evidence={ECO:0000250|UniProtKB:Q92562};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-
CC bisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-
CC inositol 4-phosphate) + phosphate; Xref=Rhea:RHEA:22764,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:58178,
CC ChEBI:CHEBI:58456; EC=3.1.3.36;
CC Evidence={ECO:0000250|UniProtKB:Q92562};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22765;
CC Evidence={ECO:0000250|UniProtKB:Q92562};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-
CC trisphosphate) + H2O = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-
CC inositol-3,4-bisphosphate) + phosphate; Xref=Rhea:RHEA:25528,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:57658,
CC ChEBI:CHEBI:57836; EC=3.1.3.86;
CC Evidence={ECO:0000250|UniProtKB:Q92562};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25529;
CC Evidence={ECO:0000250|UniProtKB:Q92562};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + O-phospho-L-seryl-[protein] = L-seryl-[protein] +
CC phosphate; Xref=Rhea:RHEA:20629, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15377, ChEBI:CHEBI:29999, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:83421; EC=3.1.3.16;
CC Evidence={ECO:0000250|UniProtKB:Q92562};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:20630;
CC Evidence={ECO:0000250|UniProtKB:Q92562};
CC -!- SUBUNIT: Component of the PI(3,5)P2 regulatory complex/PAS complex, at
CC least composed of PIKFYVE, FIG4 and VAC14 (By similarity)
CC (PubMed:19037259). VAC14 nucleates the assembly of the complex and
CC serves as a scaffold by pentamerizing into a star-shaped structure,
CC which can bind a single copy each of PIKFYVE and FIG4 and coordinates
CC their activities (By similarity). {ECO:0000250|UniProtKB:Q92562,
CC ECO:0000269|PubMed:19037259}.
CC -!- SUBCELLULAR LOCATION: Endosome membrane {ECO:0000269|PubMed:19037259}.
CC Note=Localization requires VAC14 and PIKFYVE.
CC {ECO:0000269|PubMed:19037259}.
CC -!- TISSUE SPECIFICITY: Wide-spread. {ECO:0000269|PubMed:17572665}.
CC -!- DISEASE: Note=Defects in Fig4 are the cause of the pale tremor
CC phenotype which is a multi-organ disorder with neuronal degeneration in
CC the central nervous system, peripheral neuronopathy and diluted
CC pigmentation. At postnatal day three (P3), affected homozygotes have
CC diluted pigmentation and reduced size. Intentional tremor develops
CC during the second week after birth, and abnormal limb postures are
CC evident by the third week. There is impaired motor coordination, muscle
CC weakness and 'swimming' gait. There is progressive loss of mobility,
CC reduction in body weight and juvenile lethality.
CC {ECO:0000269|PubMed:17572665}.
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DR EMBL; BC015295; AAH15295.1; -; mRNA.
DR EMBL; BC031887; AAH31887.1; -; mRNA.
DR EMBL; AK172926; BAD32204.1; -; mRNA.
DR CCDS; CCDS23803.1; -.
DR RefSeq; NP_598760.1; NM_133999.1.
DR AlphaFoldDB; Q91WF7; -.
DR SMR; Q91WF7; -.
DR IntAct; Q91WF7; 1.
DR STRING; 10090.ENSMUSP00000039598; -.
DR iPTMnet; Q91WF7; -.
DR PhosphoSitePlus; Q91WF7; -.
DR EPD; Q91WF7; -.
DR MaxQB; Q91WF7; -.
DR PaxDb; Q91WF7; -.
DR PRIDE; Q91WF7; -.
DR ProteomicsDB; 270991; -.
DR ABCD; Q91WF7; 1 sequenced antibody.
DR Antibodypedia; 56156; 259 antibodies from 29 providers.
DR DNASU; 103199; -.
DR Ensembl; ENSMUST00000043814; ENSMUSP00000039598; ENSMUSG00000038417.
DR GeneID; 103199; -.
DR KEGG; mmu:103199; -.
DR UCSC; uc007exk.1; mouse.
DR CTD; 9896; -.
DR MGI; MGI:2143585; Fig4.
DR VEuPathDB; HostDB:ENSMUSG00000038417; -.
DR eggNOG; KOG1888; Eukaryota.
DR GeneTree; ENSGT00550000074943; -.
DR HOGENOM; CLU_003016_0_3_1; -.
DR InParanoid; Q91WF7; -.
DR OMA; KRKCCAH; -.
DR OrthoDB; 359616at2759; -.
DR PhylomeDB; Q91WF7; -.
DR TreeFam; TF105702; -.
DR Reactome; R-MMU-1660514; Synthesis of PIPs at the Golgi membrane.
DR Reactome; R-MMU-1660516; Synthesis of PIPs at the early endosome membrane.
DR Reactome; R-MMU-1660517; Synthesis of PIPs at the late endosome membrane.
DR BioGRID-ORCS; 103199; 4 hits in 77 CRISPR screens.
DR ChiTaRS; Fig4; mouse.
DR PRO; PR:Q91WF7; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; Q91WF7; protein.
DR Bgee; ENSMUSG00000038417; Expressed in interventricular septum and 248 other tissues.
DR Genevisible; Q91WF7; MM.
DR GO; GO:0005783; C:endoplasmic reticulum; ISO:MGI.
DR GO; GO:0010008; C:endosome membrane; ISO:MGI.
DR GO; GO:0005794; C:Golgi apparatus; ISO:MGI.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0005811; C:lipid droplet; ISO:MGI.
DR GO; GO:0055037; C:recycling endosome; ISO:MGI.
DR GO; GO:0034593; F:phosphatidylinositol bisphosphate phosphatase activity; ISO:MGI.
DR GO; GO:0034485; F:phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity; IEA:RHEA.
DR GO; GO:0043813; F:phosphatidylinositol-3,5-bisphosphate 5-phosphatase activity; IBA:GO_Central.
DR GO; GO:0004438; F:phosphatidylinositol-3-phosphatase activity; ISO:MGI.
DR GO; GO:0004439; F:phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity; IEA:RHEA.
DR GO; GO:0043812; F:phosphatidylinositol-4-phosphate phosphatase activity; ISO:MGI.
DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; IEA:RHEA.
DR GO; GO:0007626; P:locomotory behavior; IMP:MGI.
DR GO; GO:0032288; P:myelin assembly; IGI:MGI.
DR GO; GO:0042552; P:myelination; IMP:MGI.
DR GO; GO:0031642; P:negative regulation of myelination; IMP:MGI.
DR GO; GO:0048666; P:neuron development; IMP:MGI.
DR GO; GO:0046856; P:phosphatidylinositol dephosphorylation; IBA:GO_Central.
DR GO; GO:0046488; P:phosphatidylinositol metabolic process; IMP:MGI.
DR GO; GO:0043473; P:pigmentation; IMP:MGI.
DR GO; GO:0010976; P:positive regulation of neuron projection development; ISO:MGI.
DR GO; GO:0007033; P:vacuole organization; IMP:MGI.
DR InterPro; IPR043573; Fig4-like.
DR InterPro; IPR002013; SAC_dom.
DR PANTHER; PTHR45738; PTHR45738; 1.
DR Pfam; PF02383; Syja_N; 1.
DR PROSITE; PS50275; SAC; 1.
PE 1: Evidence at protein level;
KW Endosome; Hydrolase; Membrane; Neurodegeneration; Neuropathy;
KW Reference proteome.
FT CHAIN 1..907
FT /note="Polyphosphoinositide phosphatase"
FT /id="PRO_0000209744"
FT DOMAIN 154..547
FT /note="SAC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00183"
FT REGION 707..790
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 774..790
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
SQ SEQUENCE 907 AA; 103447 MW; 3C31A28BE60F2292 CRC64;
MPTAAAPIIS SVQKLVLYET RARYFLVGSN HAETKYRVLK IDRTEPKDLV VIDDRHVYTQ
QEVRELLGRL DLGNRTKMSQ KGSSGLFRAV SAFGVVGFVR FLEGYYIVLI TKRRKMADIG
GHAIYKIEDT SMIYIPNDSV RISHPDEARY LRIFQNVDLS SNFYFSYSYD LSHSLQYNLT
VLRMPLEMLK SETSKACQES FDIFEDEGLI TQGGSGVFGI SSEPYMKYVW NGELLDIIKN
TVHRDWLLYI IHGFCGQSKL LIYGRPVYVT LIARRSSRFA GTRFLKRGAN CEGDVANEVE
TEQILCDASV MSFTAGSYSS YVQVRGSVPL FWSQDISTMM PKPPITLDQA DPFAHVAALH
FDQMLQRFGS PIIILNLVKE REKRKHERIL SEELVAAVTY LNQFLPPEHT IVYIPWDMAK
YTKSKLCNVL DRLNVIAESV VKKTGFFVNR PDSYCSILRP DEKWNELGGH VIPTGRLQTG
ILRTNCVDCL DRTNTAQFMV GKCALAYQLY SLGLIDKPNL QFDTDAVRLF EELYEDHGDT
LSLQYGGSQL VHRVKTYRKI APWTQHSKDI MQTLSRYYSN AFSDADRQDS INLFLGVFHP
TEGKPHLWEL PTDFYLHHKN TMSLLPPRRS YTYWWTPEVV KHLPLPYDEV ICAANLKKLM
VKKFHRWEEE IDIHNEFFRP YELSSFDDTF CLAMTSSARD FMPKTVGIDP SPFTVRKPDE
TGKSVLGNKN TREEAVLQRK TAASAPPPPS EEAVSSSSED DSGTDREDEG SISQRSTPVK
MTDTGDSAKA TENVVQPMKE VYGVSLSSSL SEEDHSIYAR FVQLGQSQHK QDRGNQQLCS
RCSDGVIKLT PISAFSQDNI YEVQPPRVDR KSTEIFQAHI QASQGIMQPL GKEDTAMYRE
YIRNRYL
