Force transmission and SUN-KASH higher-order assembly in the LINC complex models.

Abstract

The linker of the nucleoskeleton and cytoskeleton (LINC) complex comprises of SUN (Sad-1 and UNC-84) and KASH (Klarsicht, ANC-1, SYNE homology) domain proteins, which connect the inner and outer nuclear membrane, thereby mediating the transfer of physical forces between the cytoskeleton and the nucleoskeleton. While impaired SUN and KASH proteins are associated with structural and functional cell defects, the precise mechanism of force transduction and the assembly of these proteins remain unknown. Recent studies suggested a higher order assembly of SUN and KASH instead of a more widely accepted linear trimer model for the LINC complex. In the present study, we use molecular dynamics simulations to investigate the mechanism of force transfer across the two proposed models of LINC complex assembly, namely the 3:3 linear trimer model and the 6:6 higher-order model. Employing steered molecular dynamics simulations with forces at different rates and directions on various structures, we examine the structural stability of the two models under various biologically relevant conditions. Our results suggest that both models can withstand and transfer significant levels of force while retaining their structural integrity. However, some of the structures were more stable under specific forces compared to other structures. Slower pulling rates resulted in higher mean square fluctuations of the proteins compared to the fast pulling. Interestingly, the higher-order assembly tends to provide an additional range of motion flexibility and might be more suitable for describing the interaction between SUN and KASH under compressive and shear forces. These findings offer insights into how the SUN and KASH proteins maintain the structural integrity of the nuclear membrane.