InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: EPM2A

Summary

InnateDB Protein

IDBP-97517.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

EPM2A

Protein Name

epilepsy, progressive myoclonus type 2A, Lafora disease (laforin)

Synonyms

EPM2; MELF;

Species

Homo sapiens

Ensembl Protein

ENSP00000356489

InnateDB Gene

IDBG-97515 (EPM2A)

Protein Structure

UniProt Annotation

Function

Has both dual-specificity protein phosphatase and glucan phosphatase activities. Together with the E3 ubiquitin ligase NHLRC1/malin, appears to be involved in the clearance of toxic polyglucosan and protein aggregates via multiple pathways. Dephosphorylates phosphotyrosine, phosphoserine and phosphothreonine substrates in vitro. Has also been shown to dephosphorylate MAPT. Shows strong phosphatase activity towards complex carbohydrates in vitro, avoiding glycogen hyperphosphorylation which is associated with reduced branching and formation of insoluble aggregates. Forms a complex with NHLRC1/malin and HSP70, which suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Acts as a scaffold protein to facilitate PPP1R3C/PTG ubiquitination by NHLRC1/malin. Also promotes proteasome-independent protein degradation through the macroautophagy pathway. Isoform 2, an inactive phosphatase, could function as a dominant-negative regulator for the phosphatase activity of isoform 1. {ECO:0000269PubMed:11001928, ECO:0000269PubMed:11220751, ECO:0000269PubMed:16901901, ECO:0000269PubMed:18070875, ECO:0000269PubMed:18617530, ECO:0000269PubMed:19036738, ECO:0000269PubMed:20453062, ECO:0000269PubMed:23624058}.

Subcellular Localization

Cytoplasm {ECO:0000269PubMed:11001928, ECO:0000269PubMed:11220751, ECO:0000269PubMed:11739371, ECO:0000269PubMed:17908927, ECO:0000269PubMed:18617530}. Note=Under glycogenolytic conditions localizes to the nucleus.Isoform 1: Endoplasmic reticulum. Cell membrane. Note=Primarily associated with polyribosomes at the endoplasmic reticulum, also found at the plasma membrane.Isoform 2: Endoplasmic reticulum {ECO:0000269PubMed:11883934}. Cell membrane {ECO:0000269PubMed:11883934}. Nucleus {ECO:0000269PubMed:11883934}. Note=Also found in the nucleus.Isoform 4: Cytoplasm. Nucleus.Isoform 5: Cytoplasm. Nucleus.Isoform 7: Cytoplasm.

Disease Associations

Epilepsy, progressive myoclonic 2 (EPM2) [MIM:254780]: An autosomal recessive and severe form of adolescent-onset progressive epilepsy. Typically, as seizures increase in frequency, cognitive function declines towards dementia, and affected individuals die usually within 10 years after onset. EPM2 occurs worldwide, but it is particularly common in the mediterranean countries of southern Europe and northern Africa, in southern India and in the Middle East. At the cellular level, it is characterized by accumulation of starch-like polyglucosans called Lafora bodies (LBs) that are most abundant in organs with the highest glucose metabolism: brain, heart, liver and skeletal muscle. Among other conditions involving polyglucosans, EPM2 is unique in that the inclusions are in neuronal dendrites but not axons and the forming polyglucosan fibrils are associated with the endoplasmic reticulum. {ECO:0000269PubMed:11175283, ECO:0000269PubMed:12019207, ECO:0000269PubMed:12560877, ECO:0000269PubMed:14722920, ECO:0000269PubMed:15009235, ECO:0000269PubMed:18311786, ECO:0000269PubMed:9771710, ECO:0000269PubMed:9931343}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Tissue Specificity

Expressed in heart, skeletal muscle, kidney, pancreas and brain. Isoform 4 is also expressed in the placenta. {ECO:0000269PubMed:9771710}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 24 experimentally validated interaction(s) in this database.
They are also associated with 3 interaction(s) predicted by orthology.

Experimentally validated
Total	24 [view]
Protein-Protein	22 [view]
Protein-DNA	2 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	3 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004439	phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity
GO:0004722	protein serine/threonine phosphatase activity
GO:0004725	protein tyrosine phosphatase activity
GO:0005515	protein binding
GO:0008138	protein tyrosine/serine/threonine phosphatase activity
GO:0016791	phosphatase activity
GO:0019203	carbohydrate phosphatase activity
GO:0030246	carbohydrate binding
GO:2001070	starch binding

Biological Process

GO:0005975	carbohydrate metabolic process
GO:0005977	glycogen metabolic process
GO:0005978	glycogen biosynthetic process
GO:0006006	glucose metabolic process
GO:0006470	protein dephosphorylation
GO:0006914	autophagy
GO:0007399	nervous system development
GO:0016311	dephosphorylation
GO:0035335	peptidyl-tyrosine dephosphorylation
GO:0044281	small molecule metabolic process
GO:0046855	inositol phosphate dephosphorylation
GO:0046959	habituation

Cellular Component

GO:0005634	nucleus
GO:0005737	cytoplasm
GO:0005783	endoplasmic reticulum
GO:0005829	cytosol
GO:0005844	polysome
GO:0005886	plasma membrane

Protein Structure and Domains

PDB ID

InterPro

IPR000340 Dual specificity phosphatase, catalytic domain
IPR000387 Protein-tyrosine/Dual specificity phosphatase
IPR002044 Carbohydrate binding module family 20
IPR013784 Carbohydrate-binding-like fold
IPR020422 Dual specificity phosphatase, subgroup, catalytic domain
IPR029021 Protein-tyrosine phosphatase-like

PFAM

PF00782
PF00686

PRINTS

PIRSF

SMART

SM01065
SM00195

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt

O95278