The collagen receptors mediate the attachment of a wide variety of cells to connective tissues in diverse pathophysiological contexts. The major interest of the group is the interaction between blood vessel wall collagens and the platelet surface, a process which is fundamental to haemostasis and thrombosis. Adhesion requires integrin α2β1, whereas platelet activation involves mainly Glycoprotein VI, a receptor of the immunoglobulin family.
Platelets deposited from whole blood at arterial flow rate on collagen-coated surfaces.
Left is control, showing aggregates of platelets. Right is blood treated with anti-GpVI single chain antibody, showing prevention of aggregation, whilst primary adhesion is not impaired, (Siljander et al, 2004).
We synthesise triple-helical fragments of collagens which are selective for different collagen receptors, which allows us to study α2β1 and GpVI in isolation, and have recently located the binding site in collagen III for von Willebrand factor (VWF), completing the important adhesive motifs in collagen that recognise the platelet surface. Thus we are tackling the adhesive and signalling properties of GpIb along with the collagen receptors, processes measured under physiological shear conditions using the confocal microscopes recently installed in the lab.
We are applying our collagen peptide libraries (Toolkits) to a series of collagen-binding proteins, both from the matrix and the cell-surface, and we are making a set of collagen-mimetics for diagnostic purposes.
We collaborate with Prof Willem Ouwehand (Dept Haematology; GpVI and genetics of platelet function), with Dr Birgit Leitinger and Prof Erhard
Hohenester (Imperial College; discoidin domain receptors) and with Prof
Iain Campbell and Dr John Vakonakis (Oxford; fibronectin) and various other
collagen- or platelet-related groups.
The group is funded by Medical Research Council and British Heart Foundation, with initial support (2003/5) for peptide synthesis from
Wellcome Trust.
Current Lab members (July 2010)
Dominique Bihan, Samir Hamaia, Joanne-Marie Howes, Peter Kim, Nick Pugh,
David Slatter, Rachael Stone.
References
Lisman T, Raynal N, Groeneveld D, Maddox B, Peachey AR, Huizinga EG, de Groot PG, Farndale RW. A single high-affinity binding site for von Willebrand Factor in collagen III, identified using synthetic triple-
helical peptides. Blood. 2006; 108, 3753-6
Raynal N, Hamaia SW, Siljander PR, Maddox B, Peachey AR, Fernandez R, Foley LJ, Slatter DA, Jarvis GE, Farndale RW. Use of synthetic peptides to locate novel integrin alpha2beta1-binding motifs in human collagen III.
J Biol Chem. 2006;281:3821-3831
Herr AB, Farndale RW. Structural insights into the interactions between platelet receptors and fibrillar collagen. (2009) J Biol Chem.
284:19781-19785
Boilard E, Nigrovic PA, Larabee K, Watts GFM, Coblyn JS, Weinblatt ME, Massarotti EM, Remold-O'Donnell E, Farndale RW, Ware J, M. Lee DM.
Platelets amplify inflammation in arthritis via collagen-dependent
microparticle production. Science. 2010;327:580-583.
Pugh N, Simpson AMC, Smethurst PA, de Groot PhG, Raynal N, Farndale, RW. (2010) Synergism between platelet collagen receptors defined using receptor-specific collagen-mimetic peptide substrata in flowing blood.
Blood In the press