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

• Published in: Molecular biology of the cell Vol. 24; no. 3; pp. 342 - 350
• Main Authors: Simon, Dan N, Domaradzki, Tera, Hofmann, Wilma A, Wilson, Katherine L
• Format: Journal Article
• Language: English
• Published: United States The American Society for Cell Biology 01.02.2013
• Subjects: Amino Acid Motifs; Animals; Cercopithecus aethiops; COS Cells; HeLa Cells; Humans; Lamin Type A - chemistry; Lamin Type A - genetics; Lipodystrophy, Familial Partial - genetics; Mutation, Missense; Small Ubiquitin-Related Modifier Proteins - chemistry; Small Ubiquitin-Related Modifier Proteins - metabolism; SUMO-1 Protein - chemistry; SUMO-1 Protein - metabolism; Sumoylation; Ubiquitin-Protein Ligase Complexes - chemistry; Ubiquitin-Protein Ligase Complexes - metabolism
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.E12-07-0527

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.