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Structural insights into collagen binding by platelet receptor glycoprotein VI
Louris J Feitsma1, Harma C Brondijk1, Gavin E Jarvis2
1Department of Structural Biochemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Utrecht, The Netherlands; and.
Blood
|March 4, 2022
Summary
Researchers revealed the collagen-binding site on Glycoprotein VI (GPVI), crucial for platelet activation and thrombosis. This discovery clarifies GPVI-collagen interactions, aiding antithrombotic drug development.
Area of Science:
- Biochemistry
- Structural Biology
- Hematology
Background:
- Glycoprotein VI (GPVI) is key in collagen-induced platelet activation, a process implicated in thrombosis, heart attack, and stroke.
- GPVI is a promising therapeutic target for antithrombotic strategies, yet its collagen-binding mechanism was unclear.
Purpose of the Study:
- To elucidate the structural basis of GPVI's interaction with collagen.
- To identify specific residues and collagen motifs essential for GPVI binding.
Main Methods:
- X-ray crystallography of GPVI ectodomain bound to collagen peptides.
- Site-directed mutagenesis and binding assays.
- Alanine-scanning mutagenesis of collagen-related peptides.
Main Results:
- Crystal structures revealed a collagen-binding site on the GPVI D1 domain β-sheet.
- Trp76, Arg38, and Glu40 were identified as critical residues for binding to fibrillar collagens and collagen-related peptides (CRPs).
- GPVI binds to a two-chain collagen site featuring the OGPOGP motif; binding capacity is limited by steric hindrance.
Conclusions:
- The study provides the first structural evidence of the GPVI-collagen binding interface.
- Understanding this interaction is vital for developing targeted antithrombotic therapies.
- Differences in binding compared to LAIR-1 may allow for receptor-specific drug design.
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