title: Disruption of the lamin A and matrin-3 interaction by myopathic LMNA mutations.
abstract: The nuclear face of the nuclear membrane is enriched with the intermediate filament protein lamin A. Mutations in LMNA, the gene encoding lamin A, lead to a diverse set of inherited conditions including myopathies that affect both the heart and skeletal muscle. To gain insight about lamin A protein interactions, binding proteins associated with the tail of lamin A were characterized. Of 130 nuclear proteins found associated with the lamin A tail, 17 (13%) were previously described lamin A binding partners. One protein not previously linked to lamin A, matrin-3, was selected for further study, because like LMNA mutations, matrin-3 has also been implicated in inherited myopathy. Matrin-3 binds RNA and DNA and is a nucleoplasmic protein originally identified from the insoluble nuclear fraction, referred to as the nuclear matrix. Anti-matrin-3 antibodies were found to co-immunoprecipitate lamin A, and the lamin-A binding domain was mapped to the carboxy-terminal half of matrin-3. Three-dimensional mapping of the lamin A-matrin-3 interface showed that the LMNA truncating mutation Δ303, which lacks the matrin-3 binding domain, was associated with an increased distance between lamin A and matrin-3. LMNA mutant cells are known to have altered biophysical properties and the matrin-3-lamin A interface is positioned to contribute to these defects.
authors.affiliation: Department of Medicine.
authors.forename: Frederic F
authors.initials: FF
authors.lastname: Depreux
authors.affiliation: Department of Medicine, Center for Genetic Medicine, Northwestern University, Chicago, IL, 60611, USA.
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Puckelwartz
authors.affiliation: Department of Medicine.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Augustynowicz
authors.affiliation: Department of Molecular of Genetics and Cell Biology, Proteomics Core Facility.
authors.forename: Don
authors.initials: D
authors.lastname: Wolfgeher
authors.affiliation: Integrated Microscopy Facility, Office of Shared Research Facilities.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Labno
authors.affiliation: Department of Medicine.
authors.forename: Dynora
authors.initials: D
authors.lastname: Pierre-Louis
authors.affiliation: Department of Medicine.
authors.forename: Danielle
authors.initials: D
authors.lastname: Cicka
authors.affiliation: Department of Molecular of Genetics and Cell Biology.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kron
authors.affiliation: Department of Medicine.
authors.forename: James
authors.initials: J
authors.lastname: Holaska
authors.affiliation: Department of Medicine, Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA and Center for Genetic Medicine, Northwestern University, Chicago, IL, 60611, USA elizabeth.mcnally@northwestern.edu.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: McNally
mesh_terms: D000888:Antibodies, Anti-Idiotypic; D001665:Binding Sites; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D034521:Nuclear Matrix-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000888:Antibodies, Anti-Idiotypic; C494847:LMNA protein, human; D034904:Lamin Type A; C518587:MATR3 protein, human; D034521:Nuclear Matrix-Associated Proteins; D016601:RNA-Binding Proteins