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dc.contributor.authorFeitsma, Louris J
dc.contributor.authorBrondijk, Harma C
dc.contributor.authorJarvis, Gavin E
dc.contributor.authorHagemans, Dominique
dc.contributor.authorBihan, Dominique
dc.contributor.authorJerah, Natasia
dc.contributor.authorVersteeg, Marian
dc.contributor.authorFarndale, Richard W
dc.contributor.authorHuizinga, Eric G
dc.date.accessioned2022-02-10T00:30:39Z
dc.date.available2022-02-10T00:30:39Z
dc.date.issued2022-05-19
dc.identifier.issn0006-4971
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/333825
dc.description.abstractGlycoprotein 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.
dc.publisherAmerican Society of Hematology
dc.rightsAll Rights Reserved
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserved
dc.titleStructural insights into collagen binding by platelet receptor glycoprotein VI.
dc.typeArticle
dc.publisher.departmentDepartment of Biochemistry
dc.date.updated2022-02-09T11:21:32Z
prism.publicationNameBlood
dc.identifier.doi10.17863/CAM.81245
dcterms.dateAccepted2022-02-08
rioxxterms.versionofrecord10.1182/blood.2021013614
rioxxterms.versionAM
dc.contributor.orcidFeitsma, Louris J [0000-0002-8403-1108]
dc.contributor.orcidBrondijk, Harma C [0000-0002-0234-673X]
dc.contributor.orcidBihan, Dominique [0000-0002-4837-3389]
dc.contributor.orcidFarndale, Richard W [0000-0001-6130-8808]
dc.contributor.orcidHuizinga, Eric G [0000-0001-6928-8426]
dc.identifier.eissn1528-0020
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (G0601378)
pubs.funder-project-idMedical Research Council (G0400701)
pubs.funder-project-idWellcome Trust (068724/Z/02/Z)
cam.issuedOnline2022-03-04
cam.orpheus.successWed Mar 23 10:26:30 GMT 2022 - Embargo updated
cam.orpheus.counter1
cam.depositDate2022-02-09
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
rioxxterms.freetoread.startdate2023-03-04


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