Tbio EPM2A Laforin

Protein Summary

Description

Plays an important role in preventing glycogen hyperphosphorylation and the formation of insoluble aggregates, via its activity as glycogen phosphatase, and by promoting the ubiquitination of proteins involved in glycogen metabolism via its interaction with the E3 ubiquitin ligase NHLRC1/malin. Shows strong phosphatase activity towards complex carbohydrates in vitro, avoiding glycogen hyperphosphorylation which is associated with reduced branching and formation of insoluble aggregates (PubMed:16901901, PubMed:23922729, PubMed:26231210, PubMed:25538239, PubMed:25544560). Dephosphorylates phosphotyrosine and synthetic substrates, such as para-nitrophenylphosphate (pNPP), and has low activity with phosphoserine and phosphothreonine substrates (in vitro) (PubMed:11001928, PubMed:11220751, PubMed:11739371, PubMed:14532330, PubMed:16971387, PubMed:18617530, PubMed:22036712, PubMed:23922729, PubMed:14722920). Has been shown to dephosphorylate MAPT (By similarity). 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 (PubMed:23922729). Also promotes proteasome-independent protein degradation through the macroautophagy pathway (PubMed:20453062). Isoform 2: does not bind to glycogen (PubMed:18617530). Lacks phosphatase activity and might function as a dominant-negative regulator for the phosphatase activity of isoform 1 and isoform 7 (PubMed:18617530, PubMed:22036712). Isoform 7: has phosphatase activity (in vitro). This gene encodes a dual-specificity phosphatase and may be involved in the regulation of glycogen metabolism. The protein acts on complex carbohydrates to prevent glycogen hyperphosphorylation, thus avoiding the formation of insoluble aggregates. Loss-of-function mutations in this gene have been associated with Lafora disease, a rare, adult-onset recessive neurodegenerative disease, which results in myoclonus epilepsy and usually results in death several years after the onset of symptoms. The disease is characterized by the accumulation of insoluble particles called Lafora bodies, which are derived from glycogen. [provided by RefSeq, Jan 2018]

Uniprot Accession IDs

• O95278
• B3KMU5
• B4DRZ2
• O95483
• Q5T3F5
• Q6IS15
• Q8IU96
• Q8IX24
• Q8IX25
• Q9BS66
• Q9UEN2

Gene Name

• EPM2A

Ensembl ID

• ENST00000367519
• ENSP00000356489
• ENSG00000112425
• ENST00000435470
• ENSP00000405913
• ENST00000611340
• ENSP00000480268
• ENST00000618445
• ENSP00000480339
• ENST00000638262
• ENSP00000492876
• ENST00000638778
• ENSP00000491353
• ENST00000638783
• ENSP00000491338
• ENST00000639423
• ENSP00000492701
• ENST00000639465
• ENSP00000491180

Symbol

• EPM2
• MELF

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
protein domain	0.99
histone modification site profile	0.88
transcription factor binding site profile	0.75
microRNA	0.73
cellular component	0.69

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Target Illumination GWAS Analytics (TIGA)

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GENEVA

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IDG Development Level Summary

Tdark

These are targets about which virtually nothing is known. They do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 223.14   (req: < 5)

Gene RIFs: 49   (req: <= 3)

Antibodies: 507   (req: <= 50)

Tbio

These targets do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 223.14   (req: >= 5)

Gene RIFs: 49   (req: > 3)

Antibodies: 507   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 22

Tchem

Target has at least one ChEMBL compound with an activity cutoff of < 30 nM - AND - satisfies the preceding conditions

Active Ligand: 0

Tclin

Target has at least one approved drug - AND - satisfies the preceding conditions

Active Drug: 0

GWAS Traits (1)

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GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
mean platelet volume	EFO_0004584	3	2	3		82.6

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GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
mean platelet volume	EFO_0004584	3		82.6

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Orthologs (10)

1 – 5 of 10

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Chimp	EPM2A, laforin glucan phosphatase	VGNC:14789	748434
Mouse	epilepsy, progressive myoclonic epilepsy, type 2 gene alpha	MGI:1341085	13853
Rat	EPM2A, laforin glucan phosphatase	RGD:71047	114005
Dog	EPM2A, laforin glucan phosphatase	VGNC:53700	484022
Cow	EPM2A, laforin glucan phosphatase	VGNC:53790	526888

Species	Name	OMA	EggNOG	Inparanoid
Chimp	EPM2A, laforin glucan phosphatase
Mouse	epilepsy, progressive myoclonic epilepsy, type 2 gene alpha
Rat	EPM2A, laforin glucan phosphatase
Dog	EPM2A, laforin glucan phosphatase
Cow	EPM2A, laforin glucan phosphatase

Protein Structure (2 Structures, 0 AlphaFold Models)

Representation

  axes   backbone   ball+stick   cartoon   rocket   rope   spacefill

Color Scheme

  target   atomindex   bfactor   chainname   electrostatic   element   hydrophobicity   resname   sstruc

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More information can be found at RCSB PDB

1 – 2 of 2

PDB Structure Id	Ligand	Method	Resolution (Å)	Residues	Fraction of Total Protein	Pub Year	Title

PDB Structure Id	Fraction of Total Protein	Resolution	Pub Year

Pathways (9)

Reactome (9)

Disease (R-HSA-1643685)

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Data Source	Name	Explore in Pharos	Explore in Source
Reactome	Disease	1105 targets	R-HSA-1643685
Reactome	Diseases of carbohydrate metabolism	35 targets	R-HSA-5663084
Reactome	Diseases of metabolism	103 targets	R-HSA-5668914
Reactome	Glycogen metabolism	28 targets	R-HSA-8982491
Reactome	Glycogen storage diseases	17 targets	R-HSA-3229121

Name	Explore in Pharos	Explore in Source
Disease	1105 targets	R-HSA-1643685
Diseases of carbohydrate metabolism	35 targets	R-HSA-5663084
Diseases of metabolism	103 targets	R-HSA-5668914
Glycogen metabolism	28 targets	R-HSA-8982491
Glycogen storage diseases	17 targets	R-HSA-3229121

Gene Ontology Terms (28)

Functions (10)

Components (6)

Processes (12)

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GO Term	Evidence	Assigned by
carbohydrate binding	Inferred from Direct Assay (IDA)	UniProtKB
carbohydrate phosphatase activity	Inferred from Direct Assay (IDA)	UniProtKB
glycogen binding	Inferred from Direct Assay (IDA)	UniProtKB
phosphatase activity	Inferred from Direct Assay (IDA)	UniProtKB
protein serine/threonine phosphatase activity	Inferred from Direct Assay (IDA)	UniProtKB
protein tyrosine phosphatase activity	Inferred from Direct Assay (IDA)	UniProtKB
protein dimerization activity	Inferred from Physical Interaction (IPI)	UniProtKB
protein homodimerization activity	Inferred from Physical Interaction (IPI)	UniProtKB
protein tyrosine/serine/threonine phosphatase activity	Inferred from Electronic Annotation (IEA)	InterPro
starch binding	Inferred from Electronic Annotation (IEA)	InterPro

Protein-Protein Interactions (83)

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1 – 10 of 83

• See Interactions on String-DB

STBD1

Tbio

Novelty: 0.08362185

p_int: 0.999999857

p_ni: 1.2e-8

p_wrong: 1.31e-7

Score: 0.917

Data Source: BioPlex,STRINGDB

PRKAB2

Tchem

Family: Enzyme

Novelty: 0.02815065

p_int: 0.922313627

p_ni: 0.000001019

p_wrong: 0.077685354

Score: 0.844

Data Source: BioPlex,STRINGDB

NHLRC1

Tbio

Family: Enzyme

Novelty: 0.00927388

Score: 0.997

Data Source: STRINGDB

PPP1R3C

Tbio

Family: Enzyme

Novelty: 0.01784199

Score: 0.989

Data Source: Reactome,STRINGDB

GYS1

Tchem

Family: Enzyme

Novelty: 0.00721964

Score: 0.985

Data Source: Reactome,STRINGDB

GYG1

Tbio

Family: Enzyme

Novelty: 0.01446978

Score: 0.952

Data Source: Reactome,STRINGDB

GYS2

Tbio

Family: Enzyme

Novelty: 0.01522741

Score: 0.943

Data Source: Reactome,STRINGDB

UBB

Tbio

Novelty: 0.00661254

Score: 0.921

Data Source: STRINGDB

GYG2

Tbio

Family: Enzyme

Novelty: 0.01520991

Score: 0.914

Data Source: Reactome,STRINGDB

RPS27A

Tbio

Novelty: 0.00658124

Score: 0.906

Data Source: STRINGDB

Publication Statistics

PubMed Score  223.14

PubMed score by year

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PubTator Score  139.88

PubTator score by year

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Amino Acid Sequence

Residue Counts

Protein Sequence

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3D-structure
Alternative initiation
Alternative splicing
Autophagy
Carbohydrate metabolism
Cell membrane
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Endoplasmic reticulum

GWAS Trait Find Similar Targets

mean platelet volume

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adipose tissue phenotype
behavior/neurological phenotype
cardiovascular system phenotype
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endocrine/exocrine gland phenotype
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hematopoietic system phenotype
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