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Structural insights into collagen binding by platelet receptor glycoprotein VI

Feitsma, Louris J., Brondijk, Harma C., Jarvis, Gavin E., Hagemans, Dominique, Bihan, Dominique, Jerah, Natasia, Versteeg, Marian, Farndale, Richard W. and Huizinga, Eric G. (2022) Structural insights into collagen binding by platelet receptor glycoprotein VI. Blood, 139 (20). pp. 3087-3098. ISSN 0006-4971

Item Type: Article

Abstract

Glycoprotein VI (GPVI) mediates collagen-induced platelet activation after vascular damage and is an important contributor to the onset of thrombosis, heart attack, and stroke. Animal models of thrombosis have identified GPVI as a promising target for antithrombotic therapy. Although for many years the crystal structure of GPVI has been known, the essential details of its interaction with collagen have remained elusive. Here, we present crystal structures of the GPVI ectodomain bound to triple-helical collagen peptides, which reveal a collagen-binding site across the β-sheet of the D1 domain. Mutagenesis and binding studies confirm the observed binding site and identify Trp76, Arg38, and Glu40 as essential residues for binding to fibrillar collagens and collagen-related peptides (CRPs). GPVI binds a site on collagen comprising two collagen chains with the core formed by the sequence motif OGPOGP. Potent GPVI-binding peptides from Toolkit-III all contain OGPOGP; weaker binding peptides frequently contain a partial motif varying at either terminus. Alanine-scanning of peptide III-30 also identified two AGPOGP motifs that contribute to GPVI binding, but steric hindrance between GPVI molecules restricts the maximum binding capacity. We further show that no cooperative interactions could occur between two GPVI monomers binding to a stretch of (GPO)5 and that binding of ≥2 GPVI molecules to a fibril-embedded helix requires non-overlapping OGPOGP motifs. Our structure confirms the previously suggested similarity in collagen binding between GPVI and leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) but also indicates significant differences that may be exploited for the development of receptor-specific therapeutics.

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More Information

Uncontrolled Keywords: Thrombosis and Hemostasis, Vascular Biology
Related URLs:
Depositing User: Gavin Jarvis

Identifiers

Item ID: 15852
Identification Number: https://doi.org/10.1182/blood.2021013614
ISSN: 0006-4971
URI: http://sure.sunderland.ac.uk/id/eprint/15852
Official URL: https://ashpublications.org/blood/article-abstract...

Users with ORCIDS

ORCID for Gavin E. Jarvis: ORCID iD orcid.org/0000-0003-4362-1133

Catalogue record

Date Deposited: 29 Mar 2023 10:26
Last Modified: 17 Apr 2023 12:00

Contributors

Author: Gavin E. Jarvis ORCID iD
Author: Louris J. Feitsma
Author: Harma C. Brondijk
Author: Dominique Hagemans
Author: Dominique Bihan
Author: Natasia Jerah
Author: Marian Versteeg
Author: Richard W. Farndale
Author: Eric G. Huizinga

University Divisions

Faculty of Health Sciences and Wellbeing

Subjects

Sciences > Biomedical Sciences
Sciences > Pharmacy and Pharmacology
Sciences

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