Structural insights into collagen binding by platelet receptor glycoprotein VI.
Authors
Jarvis, Gavin E
Hagemans, Dominique
Jerah, Natasia
Versteeg, Marian
Publication Date
2022-05-19Journal Title
Blood
ISSN
0006-4971
Publisher
American Society of Hematology
Type
Article
This Version
AM
Metadata
Show full item recordCitation
Feitsma, L. J., Brondijk, H. C., Jarvis, G. E., Hagemans, D., Bihan, D., Jerah, N., Versteeg, M., et al. (2022). Structural insights into collagen binding by platelet receptor glycoprotein VI.. Blood https://doi.org/10.1182/blood.2021013614
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.
Sponsorship
Medical Research Council (G0601378)
Medical Research Council (G0400701)
Wellcome Trust (068724/Z/02/Z)
Embargo Lift Date
2023-03-04
Identifiers
External DOI: https://doi.org/10.1182/blood.2021013614
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333825
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.
Recommended or similar items
The current recommendation prototype on the Apollo Repository will be turned off on 03 February 2023. Although the pilot has been fruitful for both parties, the service provider IKVA is focusing on horizon scanning products and so the recommender service can no longer be supported. We recognise the importance of recommender services in supporting research discovery and are evaluating offerings from other service providers. If you would like to offer feedback on this decision please contact us on: support@repository.cam.ac.uk