title: Comparative normal mode analysis of LFA-1 integrin I-domains.
abstract: The conformational dynamics of the Inserted domain (I-domain) from the lymphocyte function-associated antigen-1 (LFA-1) was investigated by normal mode analysis of multiple structures of the low, intermediate, and high affinity states. LFA-1 is an integrin expressed on leukocytes and is of critical importance in adhesion reactions, like antigen-specific responses, homing, and diapedesis. The main ligand binding site of LFA-1 is the I-domain, which recognizes intercellular adhesion molecules (ICAMs), members of the immunoglobulin superfamily. From experimental crystal structures, a large-scale conformational change of, among others, the alpha7 helix of the I-domain has been observed leading to the proposal that these structural changes are linked to the conformational regulation of LFA-1. The results from the present calculations show that structural changes of the alpha7 helix consistent with those observed in the crystal structures are significantly sampled by the low frequency modes. This was found to be particularly true for the low affinity state of the I-domain, indicating that low frequency motions favor the conformational transition implicated in activation. However, beyond the simple downward shift of the helix implied by the crystal structures, the calculations further show that there is a noticeable swinging-out motion of the helix. The consequences of this motion are discussed in the context of integrin activation and inhibition. Moreover, significant changes in the atomic-level dynamics and in long-range correlated motions of the I-domain were found to occur upon binding of the natural ligand ICAM. These changes were more local upon binding of an allosteric inhibitor. The present study opens the question of how changes in dynamics may contribute to the long-range transmission of signal upon ICAM binding by the LFA-1 I-domain.
authors.affiliation: Laboratoire de Biophysicochimie Moléculaire, Institut de Chimie de Strasbourg, Université Louis Pasteur, BP 1032, Strasbourg, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gaillard
authors.forename: Elyette
authors.initials: E
authors.lastname: Martin
authors.forename: Eider
authors.initials: E
authors.lastname: San Sebastian
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Cossío
authors.forename: Xabier
authors.initials: X
authors.lastname: Lopez
authors.forename: Annick
authors.initials: A
authors.lastname: Dejaegere
authors.forename: Roland H
authors.initials: RH
authors.lastname: Stote
mesh_terms: D001665:Binding Sites; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1