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All rights reserved. http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/dc/elements/1.1/title BEL Framework Large Corpus Document http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/authoredBy http://www.tkuhn.ch/bel2nanopub/RAAAEW-2m0b-t4zTwTNGb1bRUGDCTB7TQd1KKqiU9nJCI#_7 http://resource.belframework.org/belframework/1.0/knowledge/large_corpus.bel http://purl.org/pav/version 1.4 http://www.tkuhn.ch/bel2nanopub/RAAAEW-2m0b-t4zTwTNGb1bRUGDCTB7TQd1KKqiU9nJCI#_6 http://www.w3.org/ns/prov#value 37 An initial conformational switch mechanism is consistent with the rapid and selective binding of a monovalent, ligand-mimetic antibody Fab fragment to IIb3 after platelet activation.38 Moreover, fluorescence resonance energy transfer studies using monoclonal antibodies bound to extracellular domains of IIb and 3 show that platelet activation is associated with a change in the relative orientation of the subunits.39 Electron micrographs of purified IIb3 have shown that fibrinogen binding to the globular head of the integrin can be triggered by interaction of a monoclonal antibody with the membrane-proximal stalk of 3.40 This proves that a long-range conformational change can be propagated along the integrin, a possible requirement for affinity modulation. It is logical to assume that IIb3 also clusters into multimers in response to cytoskeletal changes during platelet activation. A subpopulation of IIb3 already is linked to the membrane skeleton in resting platelets, and there is a wholesale redistribution of this integrin to the F-actin core cytoskeleton during platelet activation. 14 However, major cytoskeletal rearrangements do not seem necessary for initial high-affinity ligand binding to IIb3, because inhibitors of actin polymerization have a minimal effect on reversible ligand binding, although they do have a more substantial effect on irreversible binding.34 The structural changes in IIb3 responsible for interconversion between low- and high-affinity states are not known. One model posits that the signaling reactions triggered by platelet agonists cause some modification of the integrin cytoplasmic tails which is then propagated to the extracellular domains to effect ligand binding (Fig 2). Recent progress has been made in understanding the kinds of structural changes in the globular head of IIb3 that may be required. Based on model building and the functional effects of mutations, Springer41 has proposed that the N-terminal region of IIb (and other integrin subunits) conforms to the shape of a -propeller with seven blades oriented radially and pseudosymmetrically around a central axis and parallel to the plasma membrane. The ligand binding interface would lie on the top surface of the propeller (Fig 3). Tozer et al42 have proposed that a second ligand binding site is located in an N-terminal region of 3 that bears homology with an I-domain, which is, ironically, a ligand-binding module of approximately 190 amino acids inserted within certain subunits (but not IIb). Crystallographic analyses of I domains from L and M show an / fold consisting of seven -helices packed against a six-stranded -sheet. At one end of the -sheet is a cation binding MIDAS motif implicated in ligand binding (Fig 3).43,44 View larger version (80K): [in this window] [in a new window] Fig 3. A model depicting the potential changes in the extracellular domains of IIb3 that are required for high-affinity ligand binding. The top left panel shows an overhead view of the proposed -propeller domain within the N-terminal segment of IIb,41 and the top right panel shows the crystal structure of an I-domain,43 a homologue of which appears to be present in the N-terminal segment of 3.42 Open circles denote divalent cations and asterisks denote regions presumed to be directly involved in ligand binding. Thick ribbons are strands of -sheet, and coiled ribbons are -helices (adapted from Chothia and Jones172 with permission, from the Annual Review of Biochemistry, Volume 66, Copyright 1997, by Annual Reviews Inc). The bottom panels illustrate potential changes in these domains as IIb3 is converted from a resting state (left panel) to an activated state (right panel). (Adapted from Loftus and Liddington.45 Adapted and reproduced from The Journal of Clinical Investigation, 1997, Vol. 99, pp. 2302, by copyright permission of The American Society for Clinical Investigation.) 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