title: Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling.
abstract: How ligand binding alters integrin conformation in outside-in signaling, and how inside-out signals alter integrin affinity for ligand, have been mysterious. We address this with electron microscopy, physicochemical measurements, mutational introduction of disulfides, and ligand binding to alphaVbeta3 and alphaIIbbeta3 integrins. We show that a highly bent integrin conformation is physiological and has low affinity for biological ligands. Addition of a high affinity ligand mimetic peptide or Mn(2+) results in a switchblade-like opening to an extended structure. An outward swing of the hybrid domain at its junction with the I-like domain shows conformational change within the headpiece that is linked to ligand binding. Breakage of a C-terminal clasp between the alpha and beta subunits enhances Mn(2+)-induced unbending and ligand binding.
authors.affiliation: The Center for Blood Research, Departments of Pathology and Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Junichi
authors.initials: J
authors.lastname: Takagi
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Petre
authors.forename: Thomas
authors.initials: T
authors.lastname: Walz
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Springer
mesh_terms: D006801:Humans; D039302:Integrin alphaVbeta3 / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D016023:Integrins / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008345:Manganese / Q000494:pharmacology; D008854:Microscopy, Electron; D008958:Models, Molecular; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D011485:Protein Binding; D011487:Protein Conformation; D021122:Protein Subunits; D015398:Signal Transduction
chemical_list: D039302:Integrin alphaVbeta3; D016023:Integrins; D008024:Ligands; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D021122:Protein Subunits; D008345:Manganese