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Title: β-Subunit Binding Is Sufficient for Ligands to Open the Integrin αIIbβ3 Headpiece

Journal Article · · Journal of Biological Chemistry
 [1];  [1];  [2];  [1];  [1]
  1. Harvard Medical School, Boston, MA (United States)
  2. Harvard Medical School, Boston, MA (United States); New York Structural Biology Center, New York, NY (United States)
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The platelet integrin αIIbβ3 binds to a KQAGDV motif at the fibrinogen γ-chain C terminus and to RGD motifs present in loops in many extracellular matrix proteins. These ligands bind in a groove between the integrin α and β-subunits; the basic Lys or Arg side chain hydrogen bonds to the αIIb-subunit, and the acidic Asp side chain coordinates to a metal ion held by the β3-subunit. Ligand binding induces headpiece opening, with conformational change in the β-subunit. During this opening, RGD slides in the ligand-binding pocket toward αIIb, with movement of the βI-domain β1-α1 loop toward αIIb, enabling formation of direct, charged hydrogen bonds between the Arg side chain and αIIb. Here we test whether ligand interactions with β3 suffice for stable ligand binding and headpiece opening. We find that the AGDV tetrapeptide from KQAGDV binds to the αIIbβ3 headpiece with affinity comparable with the RGDSP peptide from fibronectin. AGDV induced complete headpiece opening in solution as shown by increase in hydrodynamic radius. Soaking of AGDV into closed αIIbβ3 headpiece crystals induced intermediate states similarly to RGDSP. AGDV has very little contact with the α-subunit. Furthermore, as measured by epitope exposure, AGDV, like the fibrinogen γ C-terminal peptide and RGD, caused integrin extension on the cell surface. Thus, pushing by the β3-subunit on Asp is sufficient for headpiece opening and ligand sliding, and no pulling by the αIIb subunit on Arg is required.

Research Organization:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Inst. of Health
Grant/Contract Number:
AC02-06CH11357; HL103526; ACB-12002; AGM-12006
OSTI ID:
1252769
Journal Information:
Journal of Biological Chemistry, Vol. 291, Issue 9; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 20 works
Citation information provided by
Web of Science

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Cited By (2)

The Importance of Detail: How Differences in Ligand Structures Determine Distinct Functional Responses in Integrin α v β 3 journal March 2019
Relating conformation to function in integrin α 5 β 1 journal June 2016

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
fibrinogen
hemostasis
integrin
platelet
receptor
allostery
conformation
structure