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Lamin A tail modification by SUMO1 is disrupted by familial partial lipodystrophy-causing mutations.

Abstract
Lamin filaments are major components of the nucleoskeleton that bind LINC complexes and many nuclear membrane proteins. The tail domain of lamin A directly binds 21 known partners, including actin, emerin, and SREBP1, but how these interactions are regulated is unknown. We report small ubiquitin-like modifier 1 (SUMO1) as a major new posttranslational modification of the lamin A tail. Two SUMO1 modification sites were identified based on in vitro SUMOylation assays and studies of Cos-7 cells. One site (K420) matches the SUMO1 target consensus; the other (K486) does not. On the basis of the position of K486 on the lamin A Ig-fold, we hypothesize the SUMO1 E2 enzyme recognizes a folded structure-dependent motif that includes residues genetically linked to familial partial lipodystrophy (FPLD). Supporting this model, SUMO1-modification of the lamin A tail is reduced by two FPLD-causing mutations, G465D and K486N, and by single mutations in acidic residues E460 and D461. These results suggest a novel mode of functional control over lamin A in cells.
AuthorsDan N Simon, Tera Domaradzki, Wilma A Hofmann, Katherine L Wilson
JournalMolecular biology of the cell (Mol Biol Cell) Vol. 24 Issue 3 Pg. 342-50 (Feb 2013) ISSN: 1939-4586 [Electronic] United States
PMID23243001 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • LMNA protein, human
  • Lamin Type A
  • SUMO-1 Protein
  • SUMO1 protein, human
  • SUMO2 protein, human
  • Small Ubiquitin-Related Modifier Proteins
  • Ubiquitin-Protein Ligase Complexes
Topics
  • Amino Acid Motifs
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • HeLa Cells
  • Humans
  • Lamin Type A (chemistry, genetics)
  • Lipodystrophy, Familial Partial (genetics)
  • Mutation, Missense
  • SUMO-1 Protein (chemistry, metabolism)
  • Small Ubiquitin-Related Modifier Proteins (chemistry, metabolism)
  • Sumoylation
  • Ubiquitin-Protein Ligase Complexes (chemistry, metabolism)

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