Conformation Coupling Between The I-like Domain Alpha7 Helix And The Hybrid Domain Of Beta3 Integrins

Abstract

Integrins are αβ heterodimers that mediate cell adhesion and transduce signals bidirectionally across the cell membrane. Integrins often exist in low affinity (or inactive) states for ligand binding on the cell curface, but change conformations to high affinity (or activated) states when induced by stimuli from inside or outside the cell. Crystallographic and electron microscopic studies have obtained evidence that the low affinity states correspond to bent conformations where the integrin headpiece interacts with the legs, whereas the high affinity states correspond to more extended conformations where integrins stand up, suggesting a switchblade-like unbending model for integrin activation. In this model, the key conformational changes on integrin headpiece include the swing out of the hybrid domain and the downward movement of I-like domain α7 helix. These conformational changes are suggested by crystal structures of β3 integrin headpieces. The unliganded αvβ3 headpiece displays a closed hybrid domain with the I-like α7 helix in an upper position and the pseudo-liganded αIIbβ3 headpiece shows an open hybrid domain with the I-like α7 helix in a lower position. Using molecular dynamics simulations we studied the stability of the two conformations of the I-like domain α7 helix and the hybrid domain, the transition between the two conformations in each structure, and the coupling between the conformational changes in the two structures. We observed that the β-propeller domain of the α subunit helped stabilize the hybrid domain at the close conformation. The down/upward movements of the I-like α7 helix correlated with the opening/closing of the hybrid domain. Our simulations identify key residues to the α7 helix movement and suggest the existence of intermediate conformations of the hybrid domain between the open and the close conformations.