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Open Access Research article

Lafora disease E3-ubiquitin ligase malin is related to TRIM32 at both the phylogenetic and functional level

Carlos Romá-Mateo1, Daniel Moreno1, Santiago Vernia1, Teresa Rubio1, Travis M Bridges2, Matthew S Gentry2 and Pascual Sanz1*

Author Affiliations

1 Instituto de Biomedicina de Valencia, CSIC and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Jaime Roig 11, 46010-Valencia, Spain

2 Department of Molecular and Cellular Biochemistry and Center for Structural Biology, University of Kentucky, Lexington, KY 40536-0509, USA

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BMC Evolutionary Biology 2011, 11:225  doi:10.1186/1471-2148-11-225

Published: 28 July 2011

Abstract

Background

Malin is an E3-ubiquitin ligase that is mutated in Lafora disease, a fatal form of progressive myoclonus epilepsy. In order to perform its function, malin forms a functional complex with laforin, a glucan phosphatase that facilitates targeting of malin to its corresponding substrates. While laforin phylogeny has been studied, there are no data on the evolutionary lineage of malin.

Results

After an extensive search for malin orthologs, we found that malin is present in all vertebrate species and a cephalochordate, in contrast with the broader species distribution previously reported for laforin. These data suggest that in addition to forming a functional complex, laforin and perhaps malin may also have independent functions. In addition, we found that malin shares significant identity with the E3-ubiquitin ligase TRIM32, which belongs to the tripartite-motif containing family of proteins. We present experimental evidence that both malin and TRIM32 share some substrates for ubiquitination, although they produce ubiquitin chains with different topologies. However, TRIM32-specific substrates were not reciprocally ubiquitinated by the laforin-malin complex.

Conclusions

We found that malin and laforin are not conserved in the same genomes. In addition, we found that malin shares significant identity with the E3-ubiquitin ligase TRIM32. The latter result suggests a common origin for malin and TRIM32 and provides insights into possible functional relationships between both proteins.

Keywords:
AMPK; malin; TRIM32; E3 ubiquitin ligase; phylogeny; Lafora disease