Model of coupling integrin conformational change to ligand dissociation. Stable integrin states are depicted by individual panels and state transitions by arrows connecting the panels, with solid and dashed line segments representing steps (indicated by legends at the top) supported and conjectured, respectively. (A–F) A bent α_Lβ₂ with an inactive αA domain (A) binds ICAM-1 with a low on rate (B). Pulled by a force (C), its αA domain is progressively activated to the intermediate (inter.)-lived (D) and long-lived (E) state followed by βA domain activation, hybrid domain swing out, and αβ leg separation (F), while keeping its bent conformation. Bent α_Lβ₂ with a differentially activated αA domain may either dissociate at different off rates or unbend, as indicated by arrows between panels. (G–L) An extended α_Lβ₂ with an inactive αA domain (G) binds ICAM-1 with both high on rate and off rate (H). Pulled by a force (I), its αA domain is progressively activated to the intermediate-lived (J) and long-lived (K) state more easily than in bent α_Lβ₂ followed by βA domain activation, hybrid domain swing out, and αβ leg separation (L) at faster rates than those for bent α_Lβ₂. Extended α_Lβ₂ with a differentially activated αA domain may either dissociate at different off rates or bend as indicated by the arrows between the panels. Just as association and dissociation are reversible, so are bending and unbending. Similarly, αA domain activation or deactivation, hybrid domain swing in/out, and αβ leg separation/closure are reversible. Unliganded integrin can still bend (G→A) or extend (A→G) in a spontaneous or inside-out signaling-dependent manner.