Molecular Mechanisms of Mechanotransduction through LINC Complexes

Abstract

The coupling of the cytoskeleton and nucleoskeleton is ultimately mediated by LINC complexes that are formed by a strong interaction between SUN domain and KASH domain proteins in the nuclear envelope. Their pivotal roles in cellular mechanotransduction and nuclear positioning have only been identified after their discovery in the past decade. Many cardiac and skeletal diseases have been attributed to the malfunction of components of LINC complexes and deletions of SUN1/2 proteins or KASH 1/2 have been proven lethal in mice. Despite their crucial roles in cellular mechanotransduction, the underlying molecular mechanisms explaining the role of these complexes in disease are yet to be explored.In this study, we employ molecular dynamics methods to explore the mechanisms of force transmission through SUN-KASH complexes. We simulate cytoskeletal forces acting on SUN-KASH complexes by performing constant force simulations on the available crystal structure of SUN2-KASH2 complexes. We examine the role of a covalent disulfide bond formed between SUN and KASH proteins and shed light on the role of metal ion binding in the function of the SUN-KASH complex under forces.Our results show that the covalent disulfide bond between two highly conserved cysteine residues of SUN2 and KASH2 is critical for the stability of these complexes under cytoskeletal forces. Furthermore, our results suggest that the transmission of forces to the nucleus mediated by SUN-KASH complexes is reliant on the formation of this covalent bond between the two conserved cysteine residues. Finally, we propose that metal ion binding may be involved in the regulation of SUN-KASH interactions, and the transmission of forces to the nucleus.