Glycoprotein VI (GPVI) is essential to the start of thrombosis, heart attack, and stroke by mediating collagen-induced platelet activation following arterial injury. GPVI has been identified as a viable target for antithrombotic treatment in animal thrombosis models. Although the crystal structure of GPVI has been known for many years, the critical features of its interaction with collagen have remained a mystery. For a study, researchers exhibited crystal structures of the GPVI ectodomain coupled to triple-helical collagen peptides, revealing a collagen-binding site spanning the D1 domain’s -sheet. Mutagenesis and binding experiments validate the reported binding location and identify Trp76, Arg38, and Glu40 as critical residues for fibrillar collagen and collagen-related peptide binding (CRPs). GPVI attaches to a location on collagen created by the sequence motif OGPOGP and consists of two collagen chains.
All Toolkit-III GPVI-binding peptides contain OGPOGP; weaker binding peptides usually have a partial motif that varies at either terminal. Alanine scanning of peptide III-30 revealed two AGPOGP patterns that help with GPVI binding; however, steric hindrance between GPVI molecules limits the maximal binding capacity. They showed that cooperative interactions between two GPVI monomers binding to a stretch of (GPO) 5 were impossible. That binding of two GPVI molecules to a fibril-embedded helix required non-overlapping OGPOGP motifs. The structure demonstrated that GPVI and leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) bound collagen similarly but also revealed significant distinctions that might be exploited for developing receptor-specific therapies.