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

BMC Evol Biol. 2011 Jul 28;11:225. doi: 10.1186/1471-2148-11-225.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • Evolution, Molecular*
  • Humans
  • Lafora Disease / enzymology*
  • Lafora Disease / genetics
  • Molecular Sequence Data
  • Phylogeny
  • Sequence Alignment
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination
  • Vertebrates / classification
  • Vertebrates / genetics

Substances

  • Carrier Proteins
  • Transcription Factors
  • Tripartite Motif Proteins
  • NHLRC1 protein, human
  • TRIM25 protein, human
  • Ubiquitin-Protein Ligases