Biophysical Society Conference | Tahoe 2024

Molecular Biophysics of Membranes

Poster Abstracts

36-POS Board 19 NANOSCALE ORGANIZATION AND DYNAMIC OF SUN1 LINC COMPLEX AS MECHANOTRANSDUCING COORDINATOR ACROSS NUCLEAR MEMBRANES Liying Wu 1 ; Fabien Pinaud 1,2 ; 1 University of Southern California, Dept of Biological Sciences, Los Angeles, CA, USA 2 University of Southern California, Dept of Physics and Astronomy, Los Angeles, CA, USA The nucleus is a central coordinator of cellular adaption to environmental forces, and its defective mechanical responses can lead to severe diseases, such as muscular dystrophies or premature aging. At the nuclear membrane, mechanical signals are transduced via the LINC complex (SUN1, SUN2, emerin, nesprin), which bridges the space between the outer nuclear envelope (ONE) and the inner nuclear envelope (INE) to transmit bidirectional forces between the cytoskeleton and the nucleoskeleton. While considerable progress was made to understand the structure and composition of LINC complexes, how they integrate and convey mechanical signals across the two membranes of the NE remains unclear. To assess how LINC complexes might organize as a function of force, we studied the nanoscale spatial distribution and the mobility of SUN1 using single molecule tracking and 3D super-resolution microscopy, while modulating nuclear mechanics in cells. We found that SUN1 protomers rapidly assemble as trimers after ER membrane insertion and accumulate as slow diffusing homo-trimers (33%) and near-immobile nanoclusters (61%) at the INE. Mechanical challenges to the nucleus induce an increase mobility of SUN1 and a local de-clustering of SUN1 homotrimers in a SUN1/nesprin interaction-dependent manner. We also identified multiple amino acid residues in SUN1 that participate in two distinct force transmission steps across the NE: (i) force transfer initiation at the ONE via SUN1/nesprin contacts and (ii) force transfer regulation across the NE by the SUN1 coiled-coil backbone, via (de)clustering of SUN1. Those residues and the clustering state of SUN1 homotrimers directly impact the stability and the shape of the NE. Together, our research provides an initial physical model of how LINC complexes function as mechanotransducing hubs across the NE to modulate nuclear mechanics in cells.

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