title: Structural basis and kinetics of force-induced conformational changes of an αA domain-containing integrin.
abstract: BACKGROUND
  Integrin α(L)β₂ (lymphocyte function-associated antigen, LFA-1) bears force upon binding to its ligand intercellular adhesion molecule 1 (ICAM-1) when a leukocyte adheres to vascular endothelium or an antigen presenting cell (APC) during immune responses. The ligand binding propensity of LFA-1 is related to its conformations, which can be regulated by force. Three conformations of the LFA-1 αA domain, determined by the position of its α₇-helix, have been suggested to correspond to three different affinity states for ligand binding.
  
  
  RESULTS
  The kinetics of the force-driven transitions between these conformations has not been defined and dynamically coupled to the force-dependent dissociation from ligand. Here we show, by steered molecular dynamics (SMD) simulations, that the αA domain was successively transitioned through three distinct conformations upon pulling the C-terminus of its α₇-helix. Based on these sequential transitions, we have constructed a mathematical model to describe the coupling between the αA domain conformational changes of LFA-1 and its dissociation from ICAM-1 under force. Using this model to analyze the published data on the force-induced dissociation of single LFA-1/ICAM-1 bonds, we estimated the force-dependent kinetic rates of interstate transition from the short-lived to intermediate-lived and from intermediate-lived to long-lived states. Interestingly, force increased these transition rates; hence activation of LFA-1 was accelerated by pulling it via an engaged ICAM-1.
  
  
  CONCLUSIONS
  Our study defines the structural basis for mechanical regulation of the kinetics of LFA-1 αA domain conformational changes and relates these simulation results to experimental data of force-induced dissociation of single LFA-1/ICAM-1 bonds by a new mathematical model, thus provided detailed structural and kinetic characterizations for force-stabilization of LFA-1/ICAM-1 interaction.
authors.affiliation: School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Xiang
authors.forename: Cho-Yin
authors.initials: CY
authors.lastname: Lee
authors.forename: Tian
authors.initials: T
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Jizhong
authors.initials: J
authors.lastname: Lou
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhu
mesh_terms: D001696:Biomechanical Phenomena / Q000187:drug effects; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D010795:Phthalic Acids / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013997:Time Factors; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D010795:Phthalic Acids; C546917:XVA 143; D015091:beta-Alanine; D018799:Intercellular Adhesion Molecule-1