The laforin/malin E3-ubiquitin ligase complex ubiquitinates pyruvate kinase M1/M2. Issue 1 (December 2015) - Viana, Rosa
Abstract Background Lafora disease (LD, OMIM 254780) is a fatal neurodegenerative disorder produced mainly by mutations in two genes:EPM2A, encoding the dual specificity phosphatase laforin, andEPM2B, encoding the E3-ubiquitin ligase malin. Although it is known that laforin and malin may form a functional complex, the underlying molecular mechanisms of this pathology are still far from being understood. Methods In order to gain information about the substrates of the laforin/malin complex, we have carried out a yeast substrate-trapping screening, originally designed to identify substrates of protein tyrosine phosphatases. Results Our results identify the two muscular isoforms of pyruvate kinase (PKM1 and PKM2) as novel interaction partners of laforin. Conclusions We present evidence indicating that the laforin/malin complex is able to interact with and ubiquitinate both PKM1 and PKM2. This post-translational modification, although it does not affect the catalytic activity of PKM1, it impairs the nuclear localization of PKM2.