title: 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.
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Dan N
authors.initials: DN
authors.lastname: Simon
authors.forename: Tera
authors.initials: T
authors.lastname: Domaradzki
authors.forename: Wilma A
authors.initials: WA
authors.lastname: Hofmann
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Wilson
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D034904:Lamin Type A / Q000737:chemistry / Q000235:genetics*; D052496:Lipodystrophy, Familial Partial / Q000235:genetics*; D020125:Mutation, Missense; D025842:SUMO-1 Protein / Q000737:chemistry / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000737:chemistry / Q000378:metabolism; D058207:Sumoylation; D043743:Ubiquitin-Protein Ligase Complexes / Q000737:chemistry / Q000378:metabolism
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; C117909:SUMO2 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D043743:Ubiquitin-Protein Ligase Complexes