title: Forcing switch from short- to intermediate- and long-lived states of the alphaA domain generates LFA-1/ICAM-1 catch bonds.
abstract: Binding of lymphocyte function-associated antigen-1 (LFA-1) to intercellular adhesion molecule-1 (ICAM-1) mediates leukocyte adhesion under force. Using a biomembrane force probe capable of measuring single bond interactions, we showed ICAM-1 binding to LFA-1 at different conformations, including the bent conformation with the lowest affinity. We quantify how force and conformations of LFA-1 regulate its kinetics with ICAM-1. At zero-force, on-rates were substantially changed by conditions that differentially favor a bent or extended LFA-1 with a closed or open headpiece; but off-rates were identical. With increasing force, LFA-1/ICAM-1 bond lifetimes (reciprocal off-rates) first increased (catch bonds) and then decreased (slip bonds). Three states with distinct off-rates were identified from lifetime distributions. Force shifted the associated fractions from the short- to intermediate- and long-lived states, producing catch bonds at low forces, but increased their off-rates exponentially, converting catch to slip bonds at high forces. An internal ligand antagonist that blocks pulling of the α(7)-helix suppressed the intermediate-/long-lived states and eliminated catch bonds, revealing an internal catch bond between the αA and βA domains. These results elucidate an allosteric mechanism for the mechanochemistry of LFA-1/ICAM-1 binding.
authors.affiliation: Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia 30332, USA.
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: D000465:Algorithms; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000737:chemistry / Q000378:metabolism; D004533:Egtazic Acid / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry / Q000378:metabolism*; D019169:Jurkat Cells; D007700:Kinetics; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000378:metabolism*; D008274:Magnesium / Q000737:chemistry / Q000378:metabolism; D008956:Models, Chemical; D010795:Phthalic Acids / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000378:metabolism; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D016169:Lymphocyte Function-Associated Antigen-1; D010795:Phthalic Acids; D019718:Receptors, CXCR4; C546917:XVA 143; D015091:beta-Alanine; D018799:Intercellular Adhesion Molecule-1; D004533:Egtazic Acid; D008274:Magnesium; D002118:Calcium
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