title: Structure and stability of the lamin A tail domain and HGPS mutant.
abstract: Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging syndrome caused by the expression and accumulation of a mutant form of lamin A, Δ50 lamin A. As a component of the cell's nucleoskeleton, lamin A plays an important role in the mechanical stabilization of the nuclear envelope and in other nuclear functions. It is largely unknown how the characteristic 50 amino acid deletion affects the conformation of the mostly intrinsically disordered tail domain of lamin A. Here we perform replica exchange molecular dynamics simulations of the tail domain and determine an ensemble of semi-stable structures. Based on these structures we show that the ZMPSTE 24 cleavage site on the precursor form of the lamin A tail domain orients itself in such a way as to facilitate cleavage during the maturation process. We confirm our simulated structures by comparing the thermodynamic properties of the ensemble structures to in vitro stability measurements. Using this combination of experimental and computational techniques, we compare the size, heterogeneity of size, thermodynamic stability of the Ig-fold, as well as the mechanisms of force-induced denaturation. Our data shows that the Δ50 lamin A tail domain is more compact and displays less heterogeneity than the mature lamin A tail domain. Altogether these results suggest that the altered structure and stability of the tail domain can explain changed protein-protein and protein-DNA interactions and may represent an etiology of the disease. Also, this study provides the first molecular structure(s) of the lamin A tail domain, which is confirmed by thermodynamic tests in experiment.
authors.affiliation: Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, 77 Mass. Ave., Room 1-235A&B, Cambridge, MA 02139, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Qin
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kalinowski
authors.forename: Kris Noel
authors.initials: KN
authors.lastname: Dahl
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Buehler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005470:Fluorometry; D034904:Lamin Type A / Q000737:chemistry* / Q000235:genetics*; D051379:Mice; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D011371:Progeria / Q000235:genetics*; D055550:Protein Stability; D017433:Protein Structure, Secondary
chemical_list: D034904:Lamin Type A