title: Transition from rolling to firm adhesion is regulated by the conformation of the I domain of the integrin lymphocyte function-associated antigen-1.
abstract: The integrin lymphocyte function-associated antigen-1 (alpha(L)beta(2)), which is known for its ability to mediate firm adhesion and migration, can also contribute to tethering and rolling in shear flow. The alpha(L) I domain can be mutationally locked with disulfide bonds into two distinct conformations, open and closed, which have high and low affinity for the ligand intercellular adhesion molecule 1 (ICAM-1), respectively. The wild type I domain exists primarily in the lower energy closed conformation. We have measured for the first time the effect of conformational change on adhesive behavior in shear flow. We show that wild type and locked open I domains, expressed in alpha(L)beta(2) heterodimers or as isolated domains on the cell surface, mediate rolling adhesion and firm adhesion, respectively. alpha(L)beta(2) is thus poised for the conversion of rolling to firm adhesion upon integrin activation in vivo. Isolated I domains are surprisingly more effective than alpha(L)beta(2) in interactions in shear flow, which may in part be a consequence of the presence of alpha(L)beta(2) in a bent conformation. Furthermore, the force exerted on the C-terminal alpha-helix appears to stabilize the open conformation of the wild type isolated I domain and contribute to its robustness in supporting rolling. An allosteric small molecule antagonist of alpha(L)beta(2) inhibits both rolling adhesion and firm adhesion, which has important implications for its mode of action in vivo.
mesh_terms: D000199:Actins / Q000502:physiology; D019943:Amino Acid Substitution; D001665:Binding Sites; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D004492:Edetic Acid / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry / Q000502:physiology*; D020014:K562 Cells; D036904:Leukocyte Rolling / Q000502:physiology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D046911:Macromolecular Substances; D008274:Magnesium / Q000494:pharmacology; D014066:Palatine Tonsil / Q000276:immunology; D011487:Protein Conformation; D017479:Receptors, Platelet-Derived Growth Factor / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013314:Stress, Mechanical; D013816:Thermodynamics; D014162:Transfection; D014471:Umbilical Veins
chemical_list: D000199:Actins; D016169:Lymphocyte Function-Associated Antigen-1; D046911:Macromolecular Substances; D011994:Recombinant Proteins; D018799:Intercellular Adhesion Molecule-1; D004492:Edetic Acid; D017479:Receptors, Platelet-Derived Growth Factor; D008274:Magnesium