TY - JOUR
T1 - Systematic identification of pathological lamin A interactors
AU - Dittmer, Travis A.
AU - Sahni, Nidhi
AU - Kubben, Nard
AU - Hill, David E.
AU - Vidal, Marc
AU - Burgess, Rebecca C.
AU - Roukos, Vassilis
AU - Misteli, Tom
PY - 2014/5/1
Y1 - 2014/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84899687973&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84899687973&partnerID=8YFLogxK
U2 - 10.1091/mbc.E14-02-0733
DO - 10.1091/mbc.E14-02-0733
M3 - Article
C2 - 24623722
AN - SCOPUS:84899687973
SN - 1059-1524
VL - 25
SP - 1493
EP - 1510
JO - Molecular Biology of the Cell
JF - Molecular Biology of the Cell
IS - 9
ER -