Biophysical Society Thematic Meeting

Mechanobiology of Disease

Friday Speaker Abstracts

Molecular Mechanisms of Mechanotransduction through LINC Complexes

Zeinab Jahed

, Gant Luxton

, Mohammad Mofrad

University of California Berkeley, Berkeley, CA, USA,

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.