title: Systematic identification of pathological lamin A interactors.
abstract: Laminopathies are a collection of phenotypically diverse diseases that include muscular dystrophies, cardiomyopathies, lipodystrophies, and premature aging syndromes. Laminopathies are caused by >300 distinct mutations in the LMNA gene, which encodes the nuclear intermediate filament proteins lamin A and C, two major architectural elements of the mammalian cell nucleus. The genotype-phenotype relationship and the basis for the pronounced tissue specificity of laminopathies are poorly understood. Here we seek to identify on a global scale lamin A-binding partners whose interaction is affected by disease-relevant LMNA mutations. In a screen of a human genome-wide ORFeome library, we identified and validated 337 lamin A-binding proteins. Testing them against 89 known lamin A disease mutations identified 50 disease-associated interactors. Association of progerin, the lamin A isoform responsible for the premature aging disorder Hutchinson-Gilford progeria syndrome, with its partners was largely mediated by farnesylation. Mapping of the interaction sites on lamin A identified the immunoglobulin G (IgG)-like domain as an interaction hotspot and demonstrated that lamin A variants, which destabilize the Ig-like domain, affect protein-protein interactions more globally than mutations of surface residues. Analysis of a set of LMNA mutations in a single residue, which result in three phenotypically distinct diseases, identified disease-specific interactors. The results represent a systematic map of disease-relevant lamin A interactors and suggest loss of tissue-specific lamin A interactions as a mechanism for the tissue-specific appearance of laminopathic phenotypes.
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 Center for Cancer Systems Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215 Department of Genetics, Harvard Medical School, Boston, MA 02215.
authors.forename: Travis A
authors.initials: TA
authors.lastname: Dittmer
authors.forename: Nidhi
authors.initials: N
authors.lastname: Sahni
authors.forename: Nard
authors.initials: N
authors.lastname: Kubben
authors.forename: David E
authors.initials: DE
authors.lastname: Hill
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Burgess
authors.forename: Vassilis
authors.initials: V
authors.lastname: Roukos
authors.forename: Tom
authors.initials: T
authors.lastname: Misteli
mesh_terms: D045744:Cell Line, Tumor; D063990:Gene Ontology; D006801:Humans; D034904:Lamin Type A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D054876:Prenylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D057165:Proteostasis Deficiencies / Q000235:genetics; D020798:Two-Hybrid System Techniques
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A