NDLI: β-Subunit Binding Is Sufficient for Ligands to Open the Integrin $α_{IIb}β_{3}$ $Headpiece^{*}$

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β-Subunit Binding Is Sufficient for Ligands to Open the Integrin $α_{IIb}β_{3}$ $Headpiece^{*}$

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Zhu, Jianghai Springer, Timothy A. Lin, Fu-yang Eng, Edward T. Hudson, Nathan E.
Description	Author Affiliation: Lin FY ( From the Department of Biological Chemistry and Molecular Pharmacology, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.); Zhu J ( From the Department of Biological Chemistry and Molecular Pharmacology, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.); Eng ET ( From the Department of Biological Chemistry and Molecular Pharmacology, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.); Hudson NE ( From the Department of Biological Chemistry and Molecular Pharmacology, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.); Springer TA ( From the Department of Biological Chemistry and Molecular Pharmacology, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115 timothy.springer@childrens.harvard.edu.)
Abstract	The platelet integrin $α_{IIb}β_{3}$ 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 $β_{3}-subunit.$ 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 $β_{3}$ suffice for stable ligand binding and headpiece opening. We find that the AGDV tetrapeptide from KQAGDV binds to the $α_{IIb}β_{3}$ 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 $α_{IIb}β_{3}$ 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 $β_{3}-subunit$ on Asp is sufficient for headpiece opening and ligand sliding, and no pulling by the $α_{IIb}$ subunit on Arg is required.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	9
Volume Number	291
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2016-02-26
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Integrin Alpha2 Metabolism Integrin Beta3 Models, Molecular Oligopeptides Platelet Glycoprotein GPIIb-IIIa Complex Animals Binding Sites Binding, Competitive CHO Cells Cricetulus Crystallography, X-Ray Fluorescence Polarization Hydrogen Bonding Chemistry Genetics Kinetics Ligands Microscopy, Electron, Transmission Nephelometry And Turbidimetry Particle Size Ultrastructure Protein Conformation Protein Interaction Domains And Motifs Recombinant Proteins Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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