Mechanically Regulated Outside-In Activation of an I-Domain-Containing Integrin

Abstract

Integrins are heterodimeric transmembrane proteins that mediate cellular adhesion and bidirectional mechanotransductions through their conformational allostery. The allosteric pathway of an I-domain-containing integrin remains unclear because of its complexity and lack of effective experiments. For a typical I-domain-containing integrin a X b 2 , molecular dynamics simulations were employed here to investigate the conformational dynamics in the first two steps of outside-in activation, the bindings of both the external and internal ligands. Results showed that the internal ligand binding is a prerequisite to the allosteric transmission from the ato b-subunits and the exertion of external force to integrin-ligand complex. The opening state of aI domain with downward movement and lower half unfolding of a 7 -helix ensures the stable intersubunit conformational transmission through external ligand binding first and internal ligand binding later. Reverse binding order induces a, to our knowledge, novel but unstable swingout of b-subunit Hybrid domain with the retained close states of both aI and bI domains. Prebinding of external ligand greatly facilitates the following internal ligand binding and vice versa. These simulations furthered the understanding in the outside-in activation of I-domain-containing integrins from the viewpoint of internal allosteric pathways.

Integrin Conformational Dynamics and Mechanotransduction

“…Several studies have reported that force promotes integrin conformational activation by governing the transition from bent to extended conformations [ 44 , 50 , 108 , 113 , 114 , 115 , 116 ]. The main structural modifications that integrins undergo during conformational activation have been identified; however, the exact mechanisms by which force promotes the changes in integrin conformation are poorly understood.…”