Muscle dystrophy single point mutation in the 2B segment of lamin A does not affect the mechanical properties at the dimer level.
Lamin intermediate filaments at the inner nuclear membrane play a key role in mechanosensation and gene regulation processes, and further guarantee the mechanical stability of the cell's nucleus. The rod-like dimers are the elementary building blocks within the dense lamina meshwork, mainly consisting of four alpha-helical coiled-coil segments as fundamental building blocks. Several mutations in the 2B segment of the rod domain of lamin A have been linked to the disease muscle dystrophy. In these diseases, the cell nuclei have been shown to feature abnormalities in the shape and its mechanical properties, leading to torn nuclear envelopes or bleb formation. However, up to now the origin of these mechanical changes remains unknown, in particular whether or not the mutations in the rod domain influence the mechanical properties of individual dimers, or if the changes are due to effects at larger hierarchical scales. Here we report a series of large-scale molecular dynamics studies of lamin A dimer segments, systematically comparing the mechanical behavior of the wild-type protein structure and a missense mutated protein structure with the point mutation p.Glu358Lys. Our results show that the nanomechanical tensile behavior of the dimer segment does not vary under presence of this mutation, suggesting that this single point mutation in muscle dystrophy does not affect the mechanical properties of lamin at the dimer level, but probably influences higher hierarchical scales.
Zhang
Huanan
H
Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Ackbarow
Theodor
T
Buehler
Markus J
MJ
D019281:Dimerization; D034904:Lamin Type A / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D009136:Muscular Dystrophies / Q000235:genetics*; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D013314:Stress, Mechanical
D034904:Lamin Type A