5ou8
From Proteopedia
Crystal structure of Glycoprotein VI in complex with collagen-peptide (GPO)5
Structural highlights
DiseaseGPVI_HUMAN Bleeding diathesis due to glycoprotein VI deficiency. The disease is caused by mutations affecting the gene represented in this entry. FunctionGPVI_HUMAN Collagen receptor involved in collagen-induced platelet adhesion and activation. Plays a key role in platelet procoagulant activity and subsequent thrombin and fibrin formation. This procoagulant function may contribute to arterial and venous thrombus formation. The signaling pathway involves the FcR gamma-chain, the Src kinases (likely FYN or LYN) and SYK, the adapter protein LAT and leads to the activation of PLCG2.[1] [2] Publication Abstract from PubMedGlycoprotein 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 beta-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. Structural insights into collagen binding by platelet receptor glycoprotein VI.,Feitsma LJ, Brondijk HC, Jarvis GE, Hagemans D, Bihan D, Jerah N, Versteeg M, Farndale RW, Huizinga EG Blood. 2022 May 19;139(20):3087-3098. doi: 10.1182/blood.2021013614. PMID:35245360[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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