Q92562 (FIG4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	907 AA.
Sequence status	Complete.
Protein existence	Evidence 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 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
Sequence similarities	Contains 1 SAC domain.
Sequence caution	The sequence BAA13403.2 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Cellular component	Endosome Membrane
Coding sequence diversity	Polymorphism
Disease	Amyotrophic lateral sclerosis Charcot-Marie-Tooth disease Disease mutation Neurodegeneration Neuropathy
Molecular function	Hydrolase
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cell death Inferred from electronic annotation. Source: UniProtKB-KW locomotory behavior Inferred from electronic annotation. Source: Compara myelin assembly Inferred from electronic annotation. Source: Compara negative regulation of myelination Inferred from electronic annotation. Source: Compara neuron development Inferred from electronic annotation. Source: Compara pigmentation Inferred from electronic annotation. Source: Compara positive regulation of neuron projection development Inferred from electronic annotation. Source: Compara small molecule metabolic process Traceable author statement. Source: Reactome vacuole organization Inferred from electronic annotation. Source: Compara
Cellular_component	Golgi membrane Traceable author statement. Source: Reactome early endosome membrane Traceable author statement. Source: Reactome late endosome membrane Traceable author statement. Source: Reactome
Molecular_function	phosphatidylinositol-3,5-bisphosphate 5-phosphatase activity Traceable author statement. Source: Reactome phosphatidylinositol-3-phosphatase activity Inferred from electronic annotation. Source: Compara phosphatidylinositol-4-phosphate phosphatase activity Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 907	907	Polyphosphoinositide phosphatase		PRO_0000209743
Regions
	Domain	154 – 547	394	SAC
	Compositional bias	746 – 749	4	Poly-Pro
	Compositional bias	755 – 758	4	Poly-Ser
Natural variations
	Natural variant	41	1	I → T in CMT4J. Ref.7		VAR_036974
	Natural variant	48	1	D → G. Ref.8		VAR_054831
	Natural variant	53	1	D → Y in ALS11. Ref.8		VAR_054832
	Natural variant	364	1	M → L. Corresponds to variant rs2295837 [ dbSNP | Ensembl ].		VAR_020378
	Natural variant	388	1	R → G. Ref.8		VAR_054833
	Natural variant	411	1	I → V. Ref.8		VAR_054834
	Natural variant	647	1	Y → C. Ref.8		VAR_054835
	Natural variant	654	1	V → A. Ref.2 Corresponds to variant rs9885672 [ dbSNP | Ensembl ].		VAR_022826
	Natural variant	902	1	I → T. Ref.8		VAR_054836
Experimental info
	Mutagenesis	488	1	D → A: Loss of activity. Ref.5
	Sequence conflict	310	1	V → A in BAD96452. Ref.2
	Sequence conflict	453	1	S → P in BAD96452. Ref.2
	Sequence conflict	598	1	F → S in BAD96452. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Q92562 [UniParc]. Last modified February 1, 1997. Version 1. Checksum: 7B6F115C095EC332	FASTA	907	103,635
	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

References

	« Hide 'large scale' referencesShow '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. , 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.
+	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.
IPI	IPI00022022.
RefSeq	NP_055660.1. NM_014845.5.
UniGene	Hs.529959.
3D structure databases
ProteinModelPortal	Q92562.
SMR	Q92562. Positions 15-549.
ModBase	Search...
Protein-protein interaction databases
STRING	9606.ENSP00000230124.
PTM databases
PhosphoSite	Q92562.
Polymorphism databases
DMDM	2497367.
Proteomic databases
PaxDb	Q92562.
PRIDE	Q92562.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000230124; ENSP00000230124; ENSG00000112367.
GeneID	9896.
KEGG	hsa:9896.
UCSC	uc003ptt.2. human.
Organism-specific databases
CTD	9896.
GeneCards	GC06P110012.
HGNC	HGNC:16873. FIG4.
HPA	CAB017823.
MIM	609390. gene. 611228. phenotype. 612577. phenotype.
neXtProt	NX_Q92562.
Orphanet	803. Amyotrophic lateral sclerosis. 139515. Charcot-Marie-Tooth disease type 4J.
PharmGKB	PA162388528.
HUGE	Search...
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG5329.
HOGENOM	HOG000168063.
InParanoid	Q92562.
OMA	LGGCVIP.
OrthoDB	EOG48SGSD.
PhylomeDB	Q92562.
Enzyme and pathway databases
BioCyc	MetaCyc:HS12771-MONOMER.
Reactome	REACT_111217. Metabolism. REACT_112621. Metabolism.
Gene expression databases
ArrayExpress	Q92562.
Bgee	Q92562.
CleanEx	HS_FIG4.
Genevestigator	Q92562.
Family and domain databases
InterPro	IPR002013. Syja_N. [Graphical view]
Pfam	PF02383. Syja_N. 1 hit. [Graphical view]
PROSITE	PS50275. SAC. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	9896.
NextBio	37311.
SOURCE	Search...

Entry information

Entry name

FIG4_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 101 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.