Systematic identification of pathological lamin A interactors.

摘要: Laminopathies are a collection of phenotypically diverse diseases that include muscular dystrophies, cardiomyopathies, lipodystrophies, and premature aging syndromes. caused by >300 distinct mutations in the LMNA gene, which encodes nuclear intermediate filament proteins lamin A C, two major architectural elements mammalian cell nucleus. The genotype–phenotype relationship basis for pronounced tissue specificity laminopathies poorly understood. Here we seek to identify on global scale A–binding partners whose interaction is affected disease-relevant mutations. In screen human genome–wide ORFeome library, identified validated 337 proteins. Testing them against 89 known disease 50 disease-associated interactors. Association progerin, isoform responsible disorder Hutchinson–Gilford progeria syndrome, with its was largely mediated farnesylation. Mapping sites immunoglobulin G (IgG)–like domain as an hotspot demonstrated variants, destabilize Ig-like domain, affect protein–protein interactions more globally than surface residues. Analysis set single residue, result three diseases, disease-specific results represent systematic map interactors suggest loss tissue-specific mechanism appearance laminopathic phenotypes.