title: Interdependence of laforin and malin proteins for their stability and functions could underlie the molecular basis of locus heterogeneity in Lafora disease.
abstract: Lafora disease (LD), an autosomal recessive and fatal form of neurodegenerative disorder, is characterized by the presence of polyglucosan inclusions in the affected tissues including the brain. LD can be caused by defects either in the EPM2A gene coding for the laforin protein phosphatase or the NHLRC1 gene coding for the malin ubiquitin ligase. Since the clinical symptoms of LD patients representing the two genetic groups are very similar and since malin is known to interact with laforin, we were curious to examine the possibility that the two proteins regulate each other's function. Using cell biological assays we demonstrate here that (i) malin promotes its own degradation via autoubiquitination, (ii) laforin prevents the auto-degradation of malin by presenting itself as a substrate and (iii) malin preferentially degrades the phosphatase-inactive laforin monomer. Our results that laforin and malin regulate each other's stability and activity offers a novel and attractive model to explain the molecular basis of locus heterogeneity observed in LD.
authors.affiliation: Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208 016, India.
authors.forename: Shuchi
authors.initials: S
authors.lastname: Mittal
authors.forename: Mamta
authors.initials: M
authors.lastname: Upadhyay
authors.forename: Pankaj Kumar
authors.initials: PK
authors.lastname: Singh
authors.forename: Rashmi
authors.initials: R
authors.lastname: Parihar
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Ganesh
mesh_terms: D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D006801:Humans; D020192:Lafora Disease / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; C478960:NHLRC1 protein, human; D044767:Ubiquitin-Protein Ligases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human