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

Lin, Fu-Yang; Zhu, Jianghai; Eng, Edward T.; Hudson, Nathan E.; Springer, Timothy A.

doi:10.1074/jbc.M115.705624

β-Subunit Binding Is Sufficient for Ligands to Open the Integrin α_IIbβ₃ Headpiece

Journal Article · Wed Dec 02 00:00:00 EST 2015 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.M115.705624· OSTI ID:1252769

Lin, Fu-Yang ^[1]; Zhu, Jianghai ^[1]; Eng, Edward T. ^[2]; Hudson, Nathan E. ^[1]; Springer, Timothy A. ^[1]

Harvard Medical School, Boston, MA (United States)
Harvard Medical School, Boston, MA (United States); New York Structural Biology Center, New York, NY (United States)

The platelet integrin α_IIbβ₃ 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 α_IIb-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 α_IIb, with movement of the βI-domain β1-α1 loop toward α_IIb, enabling formation of direct, charged hydrogen bonds between the Arg side chain and α_IIb. 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 α_IIbβ₃ 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 α_IIbβ₃ 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 α_IIb subunit on Arg is required.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Scientific User Facilities Division

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1252769

Journal Information:: Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Journal Issue: 9 Vol. 291; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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The Importance of Detail: How Differences in Ligand Structures Determine Distinct Functional Responses in Integrin α _v β ₃ Paladino, Antonella; Civera, Monica; Curnis, Flavio Chemistry – A European Journal, Vol. 25, Issue 23 https://doi.org/10.1002/chem.201900169	journal	March 2019
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Related Subjects

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