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. Author manuscript; available in PMC: 2014 Nov 1.
Published in final edited form as: Immunol Rev. 2013 Nov;256(1):10.1111/imr.12122. doi: 10.1111/imr.12122

Fig. 2. Force-regulated integrin conformational changes.

Fig. 2

(A) Inactive, bent LFA-1 with a closed headpiece and a flexible αA domain depicted by the dotted light yellow ellipsoid moving around the solid yellow αA domain. The headpiece is closed, and the αA domain is in the inactive conformation with the α7-helix in the up position and the MIDAS in the closed conformation. (B) Priming by inside-out signaling or metal ions extends LFA-1, increasing on-rate of LFA-1 for ICAM-1 but unchanging zero-force off-rate. The intrinsic ligand (Glu310, small pink circle) on the αA domain may form weak or transient bond with the βA MIDAS. (C) Small mechanical force applied to the bent LFA-1 activates the αA domain by pulling down the αA α7 helix. This activation decreases the off-rate of bent LFA-1 for ICAM-1. (D) Force fully activates LFA-1 with activated αA and βA domains, open headpiece and extended ectodomains. Two catch bonds in series are formed under pulling force. One is the intermolecular catch bond between ICAM-1 and the αA domain; the other is the intramolecular catch bond between the αA domain and the βA domain. Force can accelerate unbending from the bent to extended state [from (A) to (B) or from (C) to (D)] but impede bending. (E) Regardless of priming, the binding of XVA143 blocks the αA and βA ligation, makes the αA domain more flexible, and pushes the βA domain α7-helix further downward, inducing hybrid domain swing-out and ectodomain extension. On-rate for ICAM-1 is reduced, but zero-force off-rate remains the same. (F) Blocking the internal ligation impairs the force transmission along the pathway that favors the αA and/or βA α7 helixes downward movements. A much larger external force applied by ICAM-1 is therefore needed to generate a similar internal force to pull down the αA α7 helix to induce the intermediate- and long-lived states, but the mechanism of forcing acceleration of dissociation dominates at such high forces, converting the LFA-1–ICAM-1 catch-slip bonds to that of slip-only. Adopted from Ref. (55).