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

The linkers of the nucleoskeleton and cytoskeleton (LINC) complex comprises Sad-1 and UNC-84 (SUN) and Klarsicht, ANC-1, SYNE homology (KASH) domain proteins, whose conserved interactions provide a physical coupling between the cytoskeleton and the nucleoskeleton, thereby mediating the transfer of physical forces across the nuclear envelope. The LINC complex can perform distinct cellular functions by pairing various KASH domain proteins with the same SUN domain protein. Recent studies have 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 various structures using forces at different rates and directions, 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, the force response of various SUN/KASH assemblies depend on the force direction and pulling rates. Slower pulling rates result in higher mean square fluctuations of the 3:3 assembly compared to the fast pulling. Interestingly, the 6:6 assembly tends to provide an additional range of motion flexibility and might be more advantageous to the structural rigidity and pliability of the nuclear envelope. These findings offer insights into how the SUN and KASH proteins maintain the structural integrity of the nuclear membrane.

Molecular models of LINC complex assembly at the nuclear envelope.

Large protein complexes assemble at the nuclear envelope to transmit mechanical signals between the cytoskeleton and nucleoskeleton. These protein complexes are known as the linkers of the nucleoskeleton and cytoskeleton complexes (LINC complexes) and are formed by the interaction of SUN and KASH domain proteins in the nuclear envelope. Ample evidence suggests that SUN-KASH complexes form higher-order assemblies to withstand and transfer forces across the nuclear envelope. Herein, we present a review of recent studies over the past few years that have shed light on the mechanisms of SUN-KASH interactions, their higher order assembly, and the molecular mechanisms of force transfer across these complexes.