title: Characterization of unfolding mechanism of human lamin A Ig fold by single-molecule force spectroscopy-implications in EDMD.
abstract: A- and B-type lamins are intermediate filament proteins constituting the nuclear lamina underneath the nuclear envelope thereby conferring proper shape and mechanical rigidity to the nucleus. Lamin proteins are also shown to be related diversely to basic nuclear processes. More than 400 mutations in human lamin A protein alone have been reported to produce at least 11 different disease conditions jointly termed as laminopathies. These mutations in lamin A are scattered throughout its helical rod domain, as well as the C-terminal domain containing the conserved Ig-fold region. The commonality of phenotypes in all these diseases is characterized by misshapen nuclei of the affected tissues which might stem from altered rigidity of the supporting lamina hence lamins. Here we have focused on autosomal dominant Emery-Dreifuss Muscular Dystrophy, one such laminopathy where R453W is the causative mutation located in the Ig domain of lamin A. We have investigated by single-molecule force spectroscopy how a stretching mechanical perturbation senses the destabilizing effect of the mutation in the lamin A Ig domain and compared the mechanoelastic properties of the mutant R453W with that of the wild-type in conjunction with steered molecular dynamics. Furthermore, we have shown the interaction of Ig domain with emerin, another key player and interacting partner in the pathogenesis of EDMD, is disrupted in the R453W mutant. This altered mechanoresistance of Ig domain itself and consequent uncoupling of lamin A-emerin interaction might underlie the altered mechanotransduction properties of EDMD affected nuclei.
authors.affiliation: Biophysics & Structural Genomics Division, Saha Institute of Nuclear Physics , 1/AF, Bidhannagar, Kolkata, West Bengal 700064, India.
authors.forename: Manindra
authors.initials: M
authors.lastname: Bera
authors.forename: Hema Chandra
authors.initials: HC
authors.lastname: Kotamarthi
authors.forename: Subarna
authors.initials: S
authors.lastname: Dutta
authors.forename: Angana
authors.initials: A
authors.lastname: Ray
authors.forename: Saptaparni
authors.initials: S
authors.lastname: Ghosh
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Bhattacharyya
authors.forename: Sri Rama Koti
authors.initials: SR
authors.lastname: Ainavarapu
authors.forename: Kaushik
authors.initials: K
authors.lastname: Sengupta
mesh_terms: D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D034904:Lamin Type A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D008565:Membrane Proteins / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D017354:Point Mutation; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D058767:Protein Unfolding; D013057:Spectrum Analysis
chemical_list: D007136:Immunoglobulins; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; C092710:emerin