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Title: Structural Basis for Platelet Collagen Responses by the Immune-type Receptor Glycoprotein VI

Abstract

Activation of circulating platelets by exposed vessel wall collagen is a primary step in the pathogenesis of heart attack and stroke, and drugs to block platelet activation have successfully reduced cardiovascular morbidity and mortality. In humans and mice, collagen activation of platelets is mediated by glycoprotein VI (GPVI), a receptor that is homologous to immune receptors but bears little sequence similarity to known matrix protein adhesion receptors. Here we present the crystal structure of the collagen-binding domain of human GPVI and characterize its interaction with a collagen-related peptide. Like related immune receptors, GPVI contains 2 immunoglobulin-like domains arranged in a perpendicular orientation. Significantly, GPVI forms a back-to-back dimer in the crystal, an arrangement that could explain data previously obtained from cell-surface GPVI inhibition studies. Docking algorithms identify 2 parallel grooves on the GPVI dimer surface as collagen-binding sites, and the orientation and spacing of these grooves precisely match the dimensions of an intact collagen fiber. These findings provide a structural basis for the ability of an immunetype receptor to generate signaling responses to collagen and for the development of GPVI inhibitors as new therapies for human cardiovascular disease.

Authors:
; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
930231
Report Number(s):
BNL-80906-2008-JA
Journal ID: ISSN 0006-4971; BLOOAW; TRN: US200822%%1410
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Blood; Journal Volume: 108
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; ADHESION; ALGORITHMS; CARDIOVASCULAR DISEASES; COLLAGEN; CONTAINERS; CRYSTAL STRUCTURE; DATA; DIMENSIONS; DIMERS; DISEASE INCIDENCE; DRUGS; GLYCOPROTEINS; HEART; HUMAN POPULATIONS; INHIBITION; INTERACTIONS; MICE; MORTALITY; ORIENTATION; PATHOGENESIS; PROTEINS; RECEPTORS; SURFACES; WALLS; national synchrotron light source

Citation Formats

Horii,K., Kahn, M., and Herr, A. Structural Basis for Platelet Collagen Responses by the Immune-type Receptor Glycoprotein VI. United States: N. p., 2006. Web. doi:10.1182/blood-2006-01-010215.
Horii,K., Kahn, M., & Herr, A. Structural Basis for Platelet Collagen Responses by the Immune-type Receptor Glycoprotein VI. United States. doi:10.1182/blood-2006-01-010215.
Horii,K., Kahn, M., and Herr, A. Sun . "Structural Basis for Platelet Collagen Responses by the Immune-type Receptor Glycoprotein VI". United States. doi:10.1182/blood-2006-01-010215.
@article{osti_930231,
title = {Structural Basis for Platelet Collagen Responses by the Immune-type Receptor Glycoprotein VI},
author = {Horii,K. and Kahn, M. and Herr, A.},
abstractNote = {Activation of circulating platelets by exposed vessel wall collagen is a primary step in the pathogenesis of heart attack and stroke, and drugs to block platelet activation have successfully reduced cardiovascular morbidity and mortality. In humans and mice, collagen activation of platelets is mediated by glycoprotein VI (GPVI), a receptor that is homologous to immune receptors but bears little sequence similarity to known matrix protein adhesion receptors. Here we present the crystal structure of the collagen-binding domain of human GPVI and characterize its interaction with a collagen-related peptide. Like related immune receptors, GPVI contains 2 immunoglobulin-like domains arranged in a perpendicular orientation. Significantly, GPVI forms a back-to-back dimer in the crystal, an arrangement that could explain data previously obtained from cell-surface GPVI inhibition studies. Docking algorithms identify 2 parallel grooves on the GPVI dimer surface as collagen-binding sites, and the orientation and spacing of these grooves precisely match the dimensions of an intact collagen fiber. These findings provide a structural basis for the ability of an immunetype receptor to generate signaling responses to collagen and for the development of GPVI inhibitors as new therapies for human cardiovascular disease.},
doi = {10.1182/blood-2006-01-010215},
journal = {Blood},
number = ,
volume = 108,
place = {United States},
year = {Sun Jan 01 00:00:00 EST 2006},
month = {Sun Jan 01 00:00:00 EST 2006}
}
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