Biophysical Society Thematic Meeting | Singapore

Mechanobiology of Disease

Friday Speaker Abstracts

Molecular Mechanisms of Mechanotransduction through LINC Complexes Zeinab Jahed 1 , Gant Luxton 2 , Mohammad Mofrad 1 . 1 University of California Berkeley, Berkeley, CA, USA, 2 University of Minnesota, Minneapolis, MN, USA. Linkers of the nucleoskeleton and cytoskeleton (LINC complexes) provide a direct physical linkage between the interior of the nucleus and the cytoplasm. The tethering of the extracellular matrix, the cytoskeleton and the nucleoskeleton mediated by these complexes allows for a direct transmission of forces to the nucleus. Transmission of forces through LINC complexes is essential for several biological functions of the cell including polarization, differentiation, division and migration and other processes dependent on nuclear deformation and positioning. Recently, mutations in these complexes have been linked to inherited cardiomyopathy, a major cause of heart disease, and Emery-Driefuss muscular dystrophy, a disorder associated with cardiomyopathy and cardiac conduction defect. Despite the numerous cardiac and skeletal functions related to LINC complex proteins, the underlying mechanisms explaining the role of these complexes in health and disease are yet to be explored. In this study, we combine computational methods along with experimental validation to elucidate the molecular mechanisms of force transmission through LINC complexes at the nuclear envelope. First, we study the force response of the complex by introducing mutations in uncharacterized regions of the complex, and directly applying mechanical forces on the complexes through molecular dynamics simulations. We then experimentally test our computational findings by introducing mutations predicted to be important in force transmission by our molecular dynamics models. We also study the effect of these mutations on the oligomer state of the complex using Z-Scan Fluorescence Fluctuation Spectroscopy. We show that specific, point mutations in components of the LINC complex can destabilize the complex under mechanical forces, or alter the oligomer state of the complex. Our findings can ultimately reveal the molecular mechanisms by which mutations in LINC complexes result in phenotypical variations in cell function that lead to diseases associated with LINC complexes.

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