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Updated: Mar 31, 2026

In Vitro Analysis of E3 Ubiquitin Ligase Function
Published on: May 14, 2021
The laforin/malin E3-ubiquitin ligase complex ubiquitinates pyruvate kinase M1/M2
Rosa Viana1, Pablo Lujan2, Pascual Sanz3
1Instituto de Biomedicina de Valencia, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Jaime Roig 11, 46010, Valencia, Spain. rviana@ibv.csic.es.
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, and EPM2B, 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.
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