Abstract
Integrins may undergo large conformational changes during activation, but the dynamic processes and pathways remain poorly understood. We used molecular dynamics to simulate forced unbending of a complete integrin αVβ3 ectodomain in both unliganded and liganded forms. Pulling the head of the integrin readily induced changes in the integrin from a bent to an extended conformation. Pulling at a cyclic RGD ligand bound to the integrin head also extended the integrin, suggesting that force can activate integrins. Interactions at the interfaces between the hybrid and β tail domains and between the hybrid and epidermal growth factor 4 domains formed the major energy barrier along the unbending pathway, which could be overcome spontaneously in ∼1 µs to yield a partially-extended conformation that tended to rebend. By comparison, a fully-extended conformation was stable. A newly-formed coordination between the αV Asp457 and the α-genu metal ion might contribute to the stability of the fully-extended conformation. These results reveal the dynamic processes and pathways of integrin conformational changes with atomic details and provide new insights into the structural mechanisms of integrin activation.
Highlights
Integrins are ab heterodimeric transmembrane receptors for cell-cell and cell-extracellular matrix adhesions [1]
Equilibration of integrin aVb3 systems The present work includes a total of .600 ns all-atom, explicitsolvent molecular dynamics (MD) simulations for four complete integrin aVb3 ectodomains (Table S1): two unliganded (U1 and U2) and two liganded forms with a cyclic RGD peptide (L1 and L2)
The MD simulations reported here have connected the static conformations with dynamic processes, added time and force information, and provided structural insights to the continuous conformational changes of the integrin aVb3 ectodomain
Summary
Integrins are ab heterodimeric transmembrane receptors for cell-cell and cell-extracellular matrix adhesions [1]. A bent conformation, where the legs are bent at the knees, or genua, between the thigh and calf-1 domains of the a subunit and between the EGF1 and EGF2 domains of the b subunit to allow the N-terminal headpiece (from the N-termini to the knees) to contact the C-terminal tailpiece (from the knees to the C-termini) (Fig. 1A), was observed in all published crystal structures of complete integrin ectodomains, including aVb3 [4,5,6,7], aIIbb3 [8], and aXb2 [9]. Electron microscopy (EM) studies have observed different global conformations for integrins under different conditions, including a bent conformation, an extended conformation with a closed headpiece, and an extended conformation with an open headpiece [11,12,13]. A deadbolt model suggests much smaller conformational changes such that the CD loop (the b hairpin loop between the b strands C and D) of the bTD acts as a regulable deadbolt, the relief of which unlocks the bA domain from the inactive state [15]
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