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

• Main Authors: Gentry Matthew S, Bridges Travis M, Rubio Teresa, Vernia Santiago, Moreno Daniel, Romá-Mateo Carlos, Sanz Pascual
• Format: Article
• Language: English
• Published: BMC 2011-07-01
• Series: BMC Evolutionary Biology
• Subjects: AMPK; malin; TRIM32; E3 ubiquitin ligase; phylogeny; Lafora disease
• Online Access: http://www.biomedcentral.com/1471-2148/11/225

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusions</p> <p>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.</p>