FIG4_HUMAN
ID FIG4_HUMAN Reviewed; 907 AA.
AC Q92562; Q53H49; Q5TCS6;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1997, sequence version 1.
DT 03-AUG-2022, entry version 169.
DE RecName: Full=Polyphosphoinositide phosphatase {ECO:0000305};
DE EC=3.1.3.- {ECO:0000269|PubMed:17556371, ECO:0000269|PubMed:33098764};
DE EC=3.1.3.36 {ECO:0000269|PubMed:17556371};
DE EC=3.1.3.86 {ECO:0000269|PubMed:17556371};
DE AltName: Full=Phosphatidylinositol 3,5-bisphosphate 5-phosphatase;
DE AltName: Full=SAC domain-containing protein 3 {ECO:0000303|PubMed:17556371};
DE AltName: Full=Serine-protein phosphatase FIG4 {ECO:0000305};
DE EC=3.1.3.16 {ECO:0000269|PubMed:33098764};
GN Name=FIG4 {ECO:0000312|HGNC:HGNC:16873};
GN Synonyms=KIAA0274, SAC3 {ECO:0000303|PubMed:17556371};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=9039502; DOI=10.1093/dnares/3.5.321;
RA Nagase T., Seki N., Ishikawa K., Ohira M., Kawarabayasi Y., Ohara O.,
RA Tanaka A., Kotani H., Miyajima N., Nomura N.;
RT "Prediction of the coding sequences of unidentified human genes. VI. The
RT coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of
RT cDNA clones from cell line KG-1 and brain.";
RL DNA Res. 3:321-329(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ALA-654.
RC TISSUE=Colon;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [5]
RP FUNCTION, SUBCELLULAR LOCATION, IDENTIFICATION IN THE PI(3,5)P2 REGULATORY
RP COMPLEX, AND MUTAGENESIS OF ASP-488.
RX PubMed=17556371; DOI=10.1074/jbc.m611678200;
RA Sbrissa D., Ikonomov O.C., Fu Z., Ijuin T., Gruenberg J., Takenawa T.,
RA Shisheva A.;
RT "Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate
RT synthesis and turnover that regulates the progression of endosomal
RT transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex.";
RL J. Biol. Chem. 282:23878-23891(2007).
RN [6]
RP IDENTIFICATION IN THE PI(3,5)P2 REGULATORY COMPLEX.
RX PubMed=18950639; DOI=10.1016/j.jmb.2008.10.009;
RA Sbrissa D., Ikonomov O.C., Fenner H., Shisheva A.;
RT "ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and Sac3
RT in a complex to promote PIKfyve activity and functionality.";
RL J. Mol. Biol. 384:766-779(2008).
RN [7] {ECO:0007744|PDB:7K1W}
RP STRUCTURE BY ELECTRON MICROSCOPY (5.10 ANGSTROMS), IDENTIFICATION IN THE
RP PI(3,5)P2 REGULATORY COMPLEX, FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS
RP OF CYS-486.
RX PubMed=33098764; DOI=10.1016/j.molcel.2020.10.003;
RA Lees J.A., Li P., Kumar N., Weisman L.S., Reinisch K.M.;
RT "Insights into Lysosomal PI(3,5)P2 Homeostasis from a Structural-
RT Biochemical Analysis of the PIKfyve Lipid Kinase Complex.";
RL Mol. Cell 80:736-743.e4(2020).
RN [8]
RP VARIANT CMT4J THR-41.
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 [9]
RP VARIANT ALS11 TYR-53, AND VARIANTS GLY-48; GLY-388; VAL-411; CYS-647 AND
RP THR-902.
RX PubMed=19118816; DOI=10.1016/j.ajhg.2008.12.010;
RA Chow C.Y., Landers J.E., Bergren S.K., Sapp P.C., Grant A.E., Jones J.M.,
RA Everett L., Lenk G.M., McKenna-Yasek D.M., Weisman L.S., Figlewicz D.,
RA Brown R.H., Meisler M.H.;
RT "Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients
RT with ALS.";
RL Am. J. Hum. Genet. 84:85-88(2009).
RN [10]
RP VARIANTS CMT4J PRO-17; THR-41 AND LYS-302, AND CHARACTERIZATION OF VARIANT
RP CMT4J LYS-302.
RX PubMed=21705420; DOI=10.1093/brain/awr148;
RA Nicholson G., Lenk G.M., Reddel S.W., Grant A.E., Towne C.F.,
RA Ferguson C.J., Simpson E., Scheuerle A., Yasick M., Hoffman S., Blouin R.,
RA Brandt C., Coppola G., Biesecker L.G., Batish S.D., Meisler M.H.;
RT "Distinctive genetic and clinical features of CMT4J: a severe neuropathy
RT caused by mutations in the PI(3,5)P(2) phosphatase FIG4.";
RL Brain 134:1959-1971(2011).
RN [11]
RP CHARACTERIZATION OF VARIANT CMT4J THR-41.
RX PubMed=21655088; DOI=10.1371/journal.pgen.1002104;
RA Lenk G.M., Ferguson C.J., Chow C.Y., Jin N., Jones J.M., Grant A.E.,
RA Zolov S.N., Winters J.J., Giger R.J., Dowling J.J., Weisman L.S.,
RA Meisler M.H.;
RT "Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-
RT Tooth disease CMT4J.";
RL PLoS Genet. 7:E1002104-E1002104(2011).
RN [12]
RP VARIANTS YVS ASP-104 AND PRO-175, AND CHARACTERIZATION OF VARIANTS YVS
RP ASP-104 AND PRO-175.
RX PubMed=23623387; DOI=10.1016/j.ajhg.2013.03.020;
RA Campeau P.M., Lenk G.M., Lu J.T., Bae Y., Burrage L., Turnpenny P.,
RA Roman Corona-Rivera J., Morandi L., Mora M., Reutter H.,
RA Vulto-van Silfhout A.T., Faivre L., Haan E., Gibbs R.A., Meisler M.H.,
RA Lee B.H.;
RT "Yunis-Varon syndrome is caused by mutations in FIG4, encoding a
RT phosphoinositide phosphatase.";
RL Am. J. Hum. Genet. 92:781-791(2013).
RN [13]
RP INVOLVEMENT IN BTOP, VARIANT BTOP VAL-783, AND CHARACTERIZATION OF VARIANT
RP BTOP VAL-783.
RX PubMed=24598713; DOI=10.1212/wnl.0000000000000241;
RA Baulac S., Lenk G.M., Dufresnois B., Ouled Amar Bencheikh B., Couarch P.,
RA Renard J., Larson P.A., Ferguson C.J., Noe E., Poirier K., Hubans C.,
RA Ferreira S., Guerrini R., Ouazzani R., El Hachimi K.H., Meisler M.H.,
RA Leguern E.;
RT "Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy
RT with polymicrogyria.";
RL Neurology 82:1068-1075(2014).
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) (PubMed:17556371,
CC PubMed:33098764). Catalyzes the dephosphorylation of
CC phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) to form
CC phosphatidylinositol 3-phosphate (PubMed:33098764). Has serine-protein
CC phosphatase activity acting on PIKfyve to stimulate its lipid kinase
CC activity, its catalytically activity being required for maximal
CC PI(3,5)P2 production (PubMed:33098764). In vitro, hydrolyzes all three
CC D5-phosphorylated polyphosphoinositide and although displaying
CC preferences for PtdIns(3,5)P2, it is capable of hydrolyzing
CC PtdIns(3,4,5)P3 and PtdIns(4,5)P2, at least in vitro (PubMed:17556371).
CC {ECO:0000269|PubMed:17556371, ECO:0000269|PubMed:33098764}.
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:0000269|PubMed:17556371,
CC ECO:0000269|PubMed:33098764};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:32956;
CC Evidence={ECO:0000269|PubMed:17556371, ECO:0000269|PubMed:33098764};
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:0000269|PubMed:17556371};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22765;
CC Evidence={ECO:0000269|PubMed:17556371};
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:0000269|PubMed:17556371};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25529;
CC Evidence={ECO:0000269|PubMed:17556371};
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:0000269|PubMed:33098764};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:20630;
CC Evidence={ECO:0000269|PubMed:33098764};
CC -!- SUBUNIT: Component of the PI(3,5)P2 regulatory complex/PAS complex, at
CC least composed of PIKFYVE, FIG4 and VAC14. VAC14 nucleates the assembly
CC of the complex and serves as a scaffold by pentamerizing into a star-
CC shaped structure, which can bind a single copy each of PIKFYVE and FIG4
CC and coordinates their activities. {ECO:0000269|PubMed:17556371,
CC ECO:0000269|PubMed:18950639, ECO:0000269|PubMed:33098764}.
CC -!- INTERACTION:
CC Q92562; Q9H8Y8: GORASP2; NbExp=3; IntAct=EBI-4290773, EBI-739467;
CC Q92562; Q08AM6: VAC14; NbExp=5; IntAct=EBI-4290773, EBI-2107455;
CC -!- SUBCELLULAR LOCATION: Endosome membrane {ECO:0000269|PubMed:17556371}.
CC Note=Localization requires VAC14 and PIKFYVE.
CC {ECO:0000269|PubMed:17556371}.
CC -!- DISEASE: Charcot-Marie-Tooth disease 4J (CMT4J) [MIM:611228]: A
CC recessive demyelinating form of Charcot-Marie-Tooth disease, a disorder
CC of the peripheral nervous system, characterized by progressive weakness
CC and atrophy, initially of the peroneal muscles and later of the distal
CC muscles of the arms. Charcot-Marie-Tooth disease is classified in two
CC main groups on the basis of electrophysiologic properties and
CC histopathology: primary peripheral demyelinating neuropathies
CC (designated CMT1 when they are dominantly inherited) and primary
CC peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are
CC characterized by severely reduced nerve conduction velocities (less
CC than 38 m/sec), segmental demyelination and remyelination with onion
CC bulb formations on nerve biopsy, slowly progressive distal muscle
CC atrophy and weakness, absent deep tendon reflexes, and hollow feet. By
CC convention autosomal recessive forms of demyelinating Charcot-Marie-
CC Tooth disease are designated CMT4. {ECO:0000269|PubMed:17572665,
CC ECO:0000269|PubMed:21655088, ECO:0000269|PubMed:21705420}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Amyotrophic lateral sclerosis 11 (ALS11) [MIM:612577]: A
CC neurodegenerative disorder affecting upper motor neurons in the brain
CC and lower motor neurons in the brain stem and spinal cord, resulting in
CC fatal paralysis. Sensory abnormalities are absent. The pathologic
CC hallmarks of the disease include pallor of the corticospinal tract due
CC to loss of motor neurons, presence of ubiquitin-positive inclusions
CC within surviving motor neurons, and deposition of pathologic
CC aggregates. The etiology of amyotrophic lateral sclerosis is likely to
CC be multifactorial, involving both genetic and environmental factors.
CC The disease is inherited in 5-10% of the cases.
CC {ECO:0000269|PubMed:19118816}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Yunis-Varon syndrome (YVS) [MIM:216340]: A severe autosomal
CC recessive disorder characterized by skeletal defects, including
CC cleidocranial dysplasia and digital anomalies, and severe neurologic
CC involvement with neuronal loss. Enlarged cytoplasmic vacuoles are found
CC in neurons, muscle, and cartilage. The disorder is usually lethal in
CC infancy. {ECO:0000269|PubMed:23623387}. Note=The disease is caused by
CC variants affecting the gene represented in this entry.
CC -!- DISEASE: Polymicrogyria, bilateral temporooccipital (BTOP)
CC [MIM:612691]: A disease characterized by temporo-occipital
CC polymicrogyria, psychiatric manifestations, and epilepsy.
CC {ECO:0000269|PubMed:24598713}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA13403.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; D87464; BAA13403.2; ALT_INIT; mRNA.
DR EMBL; AK222732; BAD96452.1; -; mRNA.
DR EMBL; AL133472; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL512303; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC041338; AAH41338.1; -; mRNA.
DR CCDS; CCDS5078.1; -.
DR RefSeq; NP_055660.1; NM_014845.5.
DR PDB; 7K1W; EM; 5.10 A; F=1-907.
DR PDBsum; 7K1W; -.
DR AlphaFoldDB; Q92562; -.
DR SMR; Q92562; -.
DR BioGRID; 115225; 23.
DR CORUM; Q92562; -.
DR IntAct; Q92562; 5.
DR MINT; Q92562; -.
DR STRING; 9606.ENSP00000230124; -.
DR DEPOD; FIG4; -.
DR iPTMnet; Q92562; -.
DR PhosphoSitePlus; Q92562; -.
DR SwissPalm; Q92562; -.
DR BioMuta; FIG4; -.
DR DMDM; 2497367; -.
DR EPD; Q92562; -.
DR jPOST; Q92562; -.
DR MassIVE; Q92562; -.
DR MaxQB; Q92562; -.
DR PaxDb; Q92562; -.
DR PeptideAtlas; Q92562; -.
DR PRIDE; Q92562; -.
DR ProteomicsDB; 75318; -.
DR TopDownProteomics; Q92562; -.
DR ABCD; Q92562; 1 sequenced antibody.
DR Antibodypedia; 56156; 259 antibodies from 29 providers.
DR DNASU; 9896; -.
DR Ensembl; ENST00000230124.8; ENSP00000230124.4; ENSG00000112367.12.
DR GeneID; 9896; -.
DR KEGG; hsa:9896; -.
DR MANE-Select; ENST00000230124.8; ENSP00000230124.4; NM_014845.6; NP_055660.1.
DR UCSC; uc003ptt.3; human.
DR CTD; 9896; -.
DR DisGeNET; 9896; -.
DR GeneCards; FIG4; -.
DR HGNC; HGNC:16873; FIG4.
DR HPA; ENSG00000112367; Low tissue specificity.
DR MalaCards; FIG4; -.
DR MIM; 216340; phenotype.
DR MIM; 609390; gene.
DR MIM; 611228; phenotype.
DR MIM; 612577; phenotype.
DR MIM; 612691; phenotype.
DR neXtProt; NX_Q92562; -.
DR OpenTargets; ENSG00000112367; -.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR Orphanet; 208441; Bilateral parasagittal parieto-occipital polymicrogyria.
DR Orphanet; 139515; Charcot-Marie-Tooth disease type 4J.
DR Orphanet; 3472; Yunis-Varon syndrome.
DR PharmGKB; PA162388528; -.
DR VEuPathDB; HostDB:ENSG00000112367; -.
DR eggNOG; KOG1888; Eukaryota.
DR GeneTree; ENSGT00550000074943; -.
DR HOGENOM; CLU_003016_0_3_1; -.
DR InParanoid; Q92562; -.
DR OrthoDB; 359616at2759; -.
DR PhylomeDB; Q92562; -.
DR TreeFam; TF105702; -.
DR BioCyc; MetaCyc:HS12771-MON; -.
DR PathwayCommons; Q92562; -.
DR Reactome; R-HSA-1660514; Synthesis of PIPs at the Golgi membrane.
DR Reactome; R-HSA-1660516; Synthesis of PIPs at the early endosome membrane.
DR Reactome; R-HSA-1660517; Synthesis of PIPs at the late endosome membrane.
DR SignaLink; Q92562; -.
DR SIGNOR; Q92562; -.
DR BioGRID-ORCS; 9896; 33 hits in 1081 CRISPR screens.
DR ChiTaRS; FIG4; human.
DR GeneWiki; Fig4; -.
DR GenomeRNAi; 9896; -.
DR Pharos; Q92562; Tbio.
DR PRO; PR:Q92562; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; Q92562; protein.
DR Bgee; ENSG00000112367; Expressed in middle temporal gyrus and 204 other tissues.
DR ExpressionAtlas; Q92562; baseline and differential.
DR Genevisible; Q92562; HS.
DR GO; GO:0031901; C:early endosome membrane; TAS:Reactome.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:Ensembl.
DR GO; GO:0010008; C:endosome membrane; IDA:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0031902; C:late endosome membrane; TAS:Reactome.
DR GO; GO:0005811; C:lipid droplet; IDA:HPA.
DR GO; GO:0055037; C:recycling endosome; IEA:Ensembl.
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; IEA:Ensembl.
DR GO; GO:0004439; F:phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity; IEA:RHEA.
DR GO; GO:0043812; F:phosphatidylinositol-4-phosphate phosphatase activity; IEA:Ensembl.
DR GO; GO:0004722; F:protein serine/threonine phosphatase activity; IEA:RHEA.
DR GO; GO:0007626; P:locomotory behavior; IEA:Ensembl.
DR GO; GO:0032288; P:myelin assembly; IEA:Ensembl.
DR GO; GO:0031642; P:negative regulation of myelination; IEA:Ensembl.
DR GO; GO:0048666; P:neuron development; IEA:Ensembl.
DR GO; GO:0006661; P:phosphatidylinositol biosynthetic process; TAS:Reactome.
DR GO; GO:0046856; P:phosphatidylinositol dephosphorylation; IBA:GO_Central.
DR GO; GO:0043473; P:pigmentation; IEA:Ensembl.
DR GO; GO:0010976; P:positive regulation of neuron projection development; IEA:Ensembl.
DR GO; GO:0007033; P:vacuole organization; IEA:Ensembl.
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 3D-structure; Amyotrophic lateral sclerosis; Charcot-Marie-Tooth disease;
KW Disease variant; Endosome; Hydrolase; Membrane; Neurodegeneration;
KW Neuropathy; Reference proteome.
FT CHAIN 1..907
FT /note="Polyphosphoinositide phosphatase"
FT /id="PRO_0000209743"
FT DOMAIN 154..547
FT /note="SAC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00183"
FT REGION 707..788
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VARIANT 17
FT /note="L -> P (in CMT4J; dbSNP:rs587777713)"
FT /evidence="ECO:0000269|PubMed:21705420"
FT /id="VAR_071957"
FT VARIANT 41
FT /note="I -> T (in CMT4J; the mutant protein is unstable;
FT low levels of the protein results from impaired interaction
FT with VAC14; dbSNP:rs121908287)"
FT /evidence="ECO:0000269|PubMed:17572665,
FT ECO:0000269|PubMed:21655088, ECO:0000269|PubMed:21705420"
FT /id="VAR_036974"
FT VARIANT 48
FT /note="D -> G (in dbSNP:rs1296748657)"
FT /evidence="ECO:0000269|PubMed:19118816"
FT /id="VAR_054831"
FT VARIANT 53
FT /note="D -> Y (in ALS11; dbSNP:rs121908290)"
FT /evidence="ECO:0000269|PubMed:19118816"
FT /id="VAR_054832"
FT VARIANT 104
FT /note="G -> D (in YVS; complete loss of function mutation;
FT dbSNP:rs397509395)"
FT /evidence="ECO:0000269|PubMed:23623387"
FT /id="VAR_070051"
FT VARIANT 175
FT /note="L -> P (in YVS; complete loss of function mutation;
FT dbSNP:rs397514707)"
FT /evidence="ECO:0000269|PubMed:23623387"
FT /id="VAR_070052"
FT VARIANT 302
FT /note="E -> K (in CMT4J; loss of function;
FT dbSNP:rs587777714)"
FT /evidence="ECO:0000269|PubMed:21705420"
FT /id="VAR_071958"
FT VARIANT 364
FT /note="M -> L (in dbSNP:rs2295837)"
FT /id="VAR_020378"
FT VARIANT 388
FT /note="R -> G (in dbSNP:rs1562667776)"
FT /evidence="ECO:0000269|PubMed:19118816"
FT /id="VAR_054833"
FT VARIANT 411
FT /note="I -> V (in dbSNP:rs959747660)"
FT /evidence="ECO:0000269|PubMed:19118816"
FT /id="VAR_054834"
FT VARIANT 647
FT /note="Y -> C (in dbSNP:rs150301327)"
FT /evidence="ECO:0000269|PubMed:19118816"
FT /id="VAR_054835"
FT VARIANT 654
FT /note="V -> A (in dbSNP:rs9885672)"
FT /evidence="ECO:0000269|Ref.2"
FT /id="VAR_022826"
FT VARIANT 783
FT /note="D -> V (in BTOP; partial loss of function;
FT dbSNP:rs587777716)"
FT /evidence="ECO:0000269|PubMed:24598713"
FT /id="VAR_071959"
FT VARIANT 902
FT /note="I -> T (in dbSNP:rs1162967341)"
FT /evidence="ECO:0000269|PubMed:19118816"
FT /id="VAR_054836"
FT MUTAGEN 486
FT /note="C->S: Loss of phosphatase activity on PIKFYVE."
FT /evidence="ECO:0000269|PubMed:33098764"
FT MUTAGEN 488
FT /note="D->A: Loss of activity."
FT /evidence="ECO:0000269|PubMed:17556371"
FT CONFLICT 310
FT /note="V -> A (in Ref. 2; BAD96452)"
FT /evidence="ECO:0000305"
FT CONFLICT 453
FT /note="S -> P (in Ref. 2; BAD96452)"
FT /evidence="ECO:0000305"
FT CONFLICT 598
FT /note="F -> S (in Ref. 2; BAD96452)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 907 AA; 103635 MW; 7B6F115C095EC332 CRC64;
MPTAAAPIIS SVQKLVLYET RARYFLVGSN NAETKYRVLK IDRTEPKDLV IIDDRHVYTQ
QEVRELLGRL DLGNRTKMGQ KGSSGLFRAV SAFGVVGFVR FLEGYYIVLI TKRRKMADIG
GHAIYKVEDT NMIYIPNDSV RVTHPDEARY LRIFQNVDLS SNFYFSYSYD LSHSLQYNLT
VLRMPLEMLK SEMTQNRQES FDIFEDEGLI TQGGSGVFGI CSEPYMKYVW NGELLDIIKS
TVHRDWLLYI IHGFCGQSKL LIYGRPVYVT LIARRSSKFA GTRFLKRGAN CEGDVANEVE
TEQILCDASV MSFTAGSYSS YVQVRGSVPL YWSQDISTMM PKPPITLDQA DPFAHVAALH
FDQMFQRFGS PIIILNLVKE REKRKHERIL SEELVAAVTY LNQFLPPEHT IVYIPWDMAK
YTKSKLCNVL DRLNVIAESV VKKTGFFVNR PDSYCSILRP DEKWNELGGC VIPTGRLQTG
ILRTNCVDCL DRTNTAQFMV GKCALAYQLY SLGLIDKPNL QFDTDAVRLF EELYEDHGDT
LSLQYGGSQL VHRVKTYRKI APWTQHSKDI MQTLSRYYSN AFSDADRQDS INLFLGVFHP
TEGKPHLWEL PTDFYLHHKN TMRLLPTRRS YTYWWTPEVI KHLPLPYDEV ICAVNLKKLI
VKKFHKYEEE IDIHNEFFRP YELSSFDDTF CLAMTSSARD FMPKTVGIDP SPFTVRKPDE
TGKSVLGNKS NREEAVLQRK TAASAPPPPS EEAVSSSSED DSGTDREEEG SVSQRSTPVK
MTDAGDSAKV TENVVQPMKE LYGINLSDGL SEEDFSIYSR FVQLGQSQHK QDKNSQQPCS
RCSDGVIKLT PISAFSQDNI YEVQPPRVDR KSTEIFQAHI QASQGIMQPL GKEDSSMYRE
YIRNRYL
