Laforin
Domain
The CBM20 domain mediates binding to cytoplasmic glycogen and to Lafora polyglucosan bodies.
Function
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:25538239, PubMed:25544560, PubMed:26231210). 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:14722920, PubMed:16971387, PubMed:18617530, PubMed:22036712, PubMed:23922729). 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).
Involvement in disease
Myoclonic epilepsy of lafora 1
MELF1
A form of progressive myoclonic epilepsy, a clinically and genetically heterogeneous group of disorders defined by the combination of action and reflex myoclonus, other types of epileptic seizures, and progressive neurodegeneration and neurocognitive impairment. MELF1 is an autosomal recessive, severe form characterized by onset of progressive neurodegeneration between 8 and 18 years of age. Initial features can include headache, myoclonic jerks, generalized seizures, and often visual hallucination. Typically, as seizures increase in frequency, cognitive function declines towards dementia, and affected individuals die usually within 10 years after onset. At the cellular level, MELF1 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.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Polyubiquitinated by NHLRC1/malin.
Phosphorylation on Ser-25 by AMPK affects the phosphatase activity of the enzyme and its ability to homodimerize and interact with NHLRC1, PPP1R3C or PRKAA2.
Sequence Similarities
Belongs to the protein-tyrosine phosphatase family.
Tissue Specificity
Expressed in heart, skeletal muscle, kidney, pancreas and brain. Isoform 4 is also expressed in the placenta.
Cellular localization
- Cytoplasm
- Under glycogenolytic conditions localizes to the nucleus.
- Isoform 1
- Cytoplasm
- Endoplasmic reticulum membrane
- Peripheral membrane protein
- Cytoplasmic side
- Cell membrane
- Colocalizes with glycogen synthase in punctate structures in the cytoplasm (PubMed:11739371, PubMed:14532330). Primarily associated with polyribosomes at the rough endoplasmic reticulum, and also detected at the plasma membrane (PubMed:11001928, PubMed:11220751, PubMed:11883934, PubMed:18311786).
- Isoform 2
- Cytoplasm
- Endoplasmic reticulum membrane
- Peripheral membrane protein
- Cytoplasmic side
- Cell membrane
- Nucleus
- Also found in the nucleus.
- Isoform 4
- Cytoplasm
- Nucleus
- Isoform 5
- Cytoplasm
- Nucleus
- Isoform 7
- Cytoplasm
Alternative names
Laforin, Glucan phosphatase, Glycogen phosphatase, Lafora PTPase, LAFPTPase, EPM2A