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Q92562 (FIG4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 111. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Polyphosphoinositide phosphatase

EC=3.1.3.-
Alternative name(s):
Phosphatidylinositol 3,5-bisphosphate 5-phosphatase
SAC domain-containing protein 3
Gene names
Name:FIG4
Synonyms:KIAA0274, SAC3
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length907 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

The PI(3,5)P2 regulatory complex regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). In vitro, hydrolyzes all three D5-phosphorylated polyphosphoinositide substrates in the order PtdIns(4,5)P2 > PtdIns(3,5)P2 > PtdIns(3,4,5)P3. Plays a role in the biogenesis of endosome carrier vesicles (ECV) / multivesicular bodies (MVB) transport intermediates from early endosomes. Ref.5

Subunit structure

Component of the PI(3,5)P2 regulatory complex/PAS complex, at least composed of PIKFYVE, FIG4 and VAC14. VAC14 nucleates the assembly of the complex and serves as a scaffold. Ref.5 Ref.6

Subcellular location

Endosome membrane. Note: Localization requires VAC14 and PIKFYVE. Ref.5

Involvement in disease

Charcot-Marie-Tooth disease 4J (CMT4J) [MIM:611228]: A recessive demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. By convention autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease are designated CMT4.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.7 Ref.9

Amyotrophic lateral sclerosis 11 (ALS11) [MIM:612577]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.8

Yunis-Varon syndrome (YVS) [MIM:216340]: A severe autosomal recessive disorder characterized by skeletal defects, including cleidocranial dysplasia and digital anomalies, and severe neurologic involvement with neuronal loss. Enlarged cytoplasmic vacuoles are found in neurons, muscle, and cartilage. The disorder is usually lethal in infancy.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10

Sequence similarities

Contains 1 SAC domain.

Sequence caution

The sequence BAA13403.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
   Cellular componentEndosome
Membrane
   Coding sequence diversityPolymorphism
   DiseaseAmyotrophic lateral sclerosis
Charcot-Marie-Tooth disease
Disease mutation
Neurodegeneration
Neuropathy
   Molecular functionHydrolase
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcell death

Inferred from electronic annotation. Source: UniProtKB-KW

locomotory behavior

Inferred from electronic annotation. Source: Ensembl

myelin assembly

Inferred from electronic annotation. Source: Ensembl

negative regulation of myelination

Inferred from electronic annotation. Source: Ensembl

neuron development

Inferred from electronic annotation. Source: Ensembl

phosphatidylinositol biosynthetic process

Traceable author statement. Source: Reactome

phosphatidylinositol-3-phosphate biosynthetic process

Traceable author statement. Source: GOC

phospholipid metabolic process

Traceable author statement. Source: Reactome

pigmentation

Inferred from electronic annotation. Source: Ensembl

positive regulation of neuron projection development

Inferred from electronic annotation. Source: Ensembl

small molecule metabolic process

Traceable author statement. Source: Reactome

vacuole organization

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentGolgi membrane

Traceable author statement. Source: Reactome

early endosome membrane

Traceable author statement. Source: Reactome

endosome membrane

Inferred from direct assay Ref.5. Source: UniProtKB

late endosome membrane

Traceable author statement. Source: Reactome

   Molecular_functionphosphatidylinositol-3,5-bisphosphate 5-phosphatase activity

Traceable author statement. Source: Reactome

phosphatidylinositol-3-phosphatase activity

Inferred from electronic annotation. Source: Ensembl

phosphatidylinositol-4-phosphate phosphatase activity

Inferred from electronic annotation. Source: Ensembl

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 907907Polyphosphoinositide phosphatase
PRO_0000209743

Regions

Domain154 – 547394SAC
Compositional bias746 – 7494Poly-Pro
Compositional bias755 – 7584Poly-Ser

Natural variations

Natural variant411I → T in CMT4J; the mutant protein is unstable; low levels of the protein results from impaired interaction with VAC14; is a hypomorphic allele. Ref.7 Ref.9
Corresponds to variant rs121908287 [ dbSNP | Ensembl ].
VAR_036974
Natural variant481D → G. Ref.8
VAR_054831
Natural variant531D → Y in ALS11. Ref.8
VAR_054832
Natural variant1041G → D in YVS; complete loss of functiom mutation. Ref.10
VAR_070051
Natural variant1751L → P in YVS; complete loss of functiom mutation. Ref.10
VAR_070052
Natural variant3641M → L.
Corresponds to variant rs2295837 [ dbSNP | Ensembl ].
VAR_020378
Natural variant3881R → G. Ref.8
VAR_054833
Natural variant4111I → V. Ref.8
VAR_054834
Natural variant6471Y → C. Ref.8
VAR_054835
Natural variant6541V → A. Ref.2
Corresponds to variant rs9885672 [ dbSNP | Ensembl ].
VAR_022826
Natural variant9021I → T. Ref.8
VAR_054836

Experimental info

Mutagenesis4881D → A: Loss of activity. Ref.5
Sequence conflict3101V → A in BAD96452. Ref.2
Sequence conflict4531S → P in BAD96452. Ref.2
Sequence conflict5981F → S in BAD96452. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Q92562 [UniParc].

Last modified February 1, 1997. Version 1.
Checksum: 7B6F115C095EC332

FASTA907103,635
        10         20         30         40         50         60 
MPTAAAPIIS SVQKLVLYET RARYFLVGSN NAETKYRVLK IDRTEPKDLV IIDDRHVYTQ 

        70         80         90        100        110        120 
QEVRELLGRL DLGNRTKMGQ KGSSGLFRAV SAFGVVGFVR FLEGYYIVLI TKRRKMADIG 

       130        140        150        160        170        180 
GHAIYKVEDT NMIYIPNDSV RVTHPDEARY LRIFQNVDLS SNFYFSYSYD LSHSLQYNLT 

       190        200        210        220        230        240 
VLRMPLEMLK SEMTQNRQES FDIFEDEGLI TQGGSGVFGI CSEPYMKYVW NGELLDIIKS 

       250        260        270        280        290        300 
TVHRDWLLYI IHGFCGQSKL LIYGRPVYVT LIARRSSKFA GTRFLKRGAN CEGDVANEVE 

       310        320        330        340        350        360 
TEQILCDASV MSFTAGSYSS YVQVRGSVPL YWSQDISTMM PKPPITLDQA DPFAHVAALH 

       370        380        390        400        410        420 
FDQMFQRFGS PIIILNLVKE REKRKHERIL SEELVAAVTY LNQFLPPEHT IVYIPWDMAK 

       430        440        450        460        470        480 
YTKSKLCNVL DRLNVIAESV VKKTGFFVNR PDSYCSILRP DEKWNELGGC VIPTGRLQTG 

       490        500        510        520        530        540 
ILRTNCVDCL DRTNTAQFMV GKCALAYQLY SLGLIDKPNL QFDTDAVRLF EELYEDHGDT 

       550        560        570        580        590        600 
LSLQYGGSQL VHRVKTYRKI APWTQHSKDI MQTLSRYYSN AFSDADRQDS INLFLGVFHP 

       610        620        630        640        650        660 
TEGKPHLWEL PTDFYLHHKN TMRLLPTRRS YTYWWTPEVI KHLPLPYDEV ICAVNLKKLI 

       670        680        690        700        710        720 
VKKFHKYEEE IDIHNEFFRP YELSSFDDTF CLAMTSSARD FMPKTVGIDP SPFTVRKPDE 

       730        740        750        760        770        780 
TGKSVLGNKS NREEAVLQRK TAASAPPPPS EEAVSSSSED DSGTDREEEG SVSQRSTPVK 

       790        800        810        820        830        840 
MTDAGDSAKV TENVVQPMKE LYGINLSDGL SEEDFSIYSR FVQLGQSQHK QDKNSQQPCS 

       850        860        870        880        890        900 
RCSDGVIKLT PISAFSQDNI YEVQPPRVDR KSTEIFQAHI QASQGIMQPL GKEDSSMYRE 


YIRNRYL 

« Hide

References

« Hide 'large scale' references
[1]"Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain."
Nagase T., Seki N., Ishikawa K., Ohira M., Kawarabayasi Y., Ohara O., Tanaka A., Kotani H., Miyajima N., Nomura N.
DNA Res. 3:321-329(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Brain.
[2]Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.
Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT ALA-654.
Tissue: Colon.
[3]"The DNA sequence and analysis of human chromosome 6."
Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. expand/collapse author list , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.
Nature 425:805-811(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Brain.
[5]"Core protein machinery for mammalian phosphatidylinositol 3,5-bisphosphate synthesis and turnover that regulates the progression of endosomal transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex."
Sbrissa D., Ikonomov O.C., Fu Z., Ijuin T., Gruenberg J., Takenawa T., Shisheva A.
J. Biol. Chem. 282:23878-23891(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, IDENTIFICATION IN THE PI(3,5)P2 REGULATORY COMPLEX, MUTAGENESIS OF ASP-488.
[6]"ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and Sac3 in a complex to promote PIKfyve activity and functionality."
Sbrissa D., Ikonomov O.C., Fenner H., Shisheva A.
J. Mol. Biol. 384:766-779(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION IN THE PI(3,5)P2 REGULATORY COMPLEX.
[7]"Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J."
Chow C.Y., Zhang Y., Dowling J.J., Jin N., Adamska M., Shiga K., Szigeti K., Shy M.E., Li J., Zhang X., Lupski J.R., Weisman L.S., Meisler M.H.
Nature 448:68-72(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT CMT4J THR-41.
[8]"Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS."
Chow C.Y., Landers J.E., Bergren S.K., Sapp P.C., Grant A.E., Jones J.M., Everett L., Lenk G.M., McKenna-Yasek D.M., Weisman L.S., Figlewicz D., Brown R.H., Meisler M.H.
Am. J. Hum. Genet. 84:85-88(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT ALS11 TYR-53, VARIANTS GLY-48; GLY-388; VAL-411; CYS-647 AND THR-902.
[9]"Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J."
Lenk G.M., Ferguson C.J., Chow C.Y., Jin N., Jones J.M., Grant A.E., Zolov S.N., Winters J.J., Giger R.J., Dowling J.J., Weisman L.S., Meisler M.H.
PLoS Genet. 7:E1002104-E1002104(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION OF VARIANT CMT4J THR-41.
[10]"Yunis-Varon syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase."
Campeau P.M., Lenk G.M., Lu J.T., Bae Y., Burrage L., Turnpenny P., Roman Corona-Rivera J., Morandi L., Mora M., Reutter H., Vulto-van Silfhout A.T., Faivre L., Haan E., Gibbs R.A., Meisler M.H., Lee B.H.
Am. J. Hum. Genet. 92:781-791(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS YVS ASP-104 AND PRO-175, CHARACTERIZATION OF VARIANTS YVS ASP-104 AND PRO-175.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
D87464 mRNA. Translation: BAA13403.2. Different initiation.
AK222732 mRNA. Translation: BAD96452.1.
AL133472, AL512303 Genomic DNA. Translation: CAI19669.1.
AL512303, AL133472 Genomic DNA. Translation: CAI42494.1.
BC041338 mRNA. Translation: AAH41338.1.
RefSeqNP_055660.1. NM_014845.5.
UniGeneHs.529959.

3D structure databases

ProteinModelPortalQ92562.
SMRQ92562. Positions 15-549.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid115225. 3 interactions.
IntActQ92562. 1 interaction.
MINTMINT-2812974.
STRING9606.ENSP00000230124.

PTM databases

PhosphoSiteQ92562.

Polymorphism databases

DMDM2497367.

Proteomic databases

PaxDbQ92562.
PRIDEQ92562.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000230124; ENSP00000230124; ENSG00000112367.
GeneID9896.
KEGGhsa:9896.
UCSCuc003ptt.2. human.

Organism-specific databases

CTD9896.
GeneCardsGC06P110012.
HGNCHGNC:16873. FIG4.
HPACAB017823.
MIM216340. phenotype.
609390. gene.
611228. phenotype.
612577. phenotype.
neXtProtNX_Q92562.
Orphanet803. Amyotrophic lateral sclerosis.
139515. Charcot-Marie-Tooth disease type 4J.
35689. Primary lateral sclerosis.
3472. Yunis-Varon syndrome.
PharmGKBPA162388528.
HUGESearch...
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG5329.
HOGENOMHOG000168063.
InParanoidQ92562.
OMARDFMPKN.
OrthoDBEOG73FQM1.
PhylomeDBQ92562.
TreeFamTF105702.

Enzyme and pathway databases

BioCycMetaCyc:HS12771-MONOMER.
ReactomeREACT_111217. Metabolism.
REACT_188937. Metabolism.

Gene expression databases

ArrayExpressQ92562.
BgeeQ92562.
CleanExHS_FIG4.
GenevestigatorQ92562.

Family and domain databases

InterProIPR002013. Syja_N.
[Graphical view]
PfamPF02383. Syja_N. 1 hit.
[Graphical view]
PROSITEPS50275. SAC. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiFig4.
GenomeRNAi9896.
NextBio37311.
PROQ92562.
SOURCESearch...

Entry information

Entry nameFIG4_HUMAN
AccessionPrimary (citable) accession number: Q92562
Secondary accession number(s): Q53H49, Q5TCS6
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: February 1, 1997
Last modified: April 16, 2014
This is version 111 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 6

Human chromosome 6: entries, gene names and cross-references to MIM