Cloning, characterization, and functional studies of human and mouse glycoprotein VI: a platelet-specific collagen receptor from the immunoglobulin superfamily

Injuries to the vessel wall and subsequent exposure of collagen from the su bendothelial matrix result in thrombus formation. In physiological conditio ns, the platelet plug limits blood loss. However, in pathologic conditions, such as rupture of atherosclerotic plaques, platelet-collagen interactions are associated with cardiovascular and cerebral vascular diseases. Platele t glycoprotein VI (GPVI) plays a crucial role in collagen-induced activatio n and aggregation of platelets, and people who are deficient in GPVI suffer from bleeding disorders. Based on the fact that GPVI is coupled to the Fc receptor (FcR)-gamma chain and thus should share homology with the FcR chai ns, the genes encoding human and mouse GPVI were identified. They belong to the immunoglobulin tig) superfamily and share 64% homology at the protein level. Functional evidence demonstrating the identity of the recombinant pr otein with GPVI was shown by binding to its natural ligand collagen; bindin g to convulxin (Cvx), a GPVI-specific ligand from snake venom; binding of a nti-GPVI IgG isolated from a patient; and association to the FcR-gamma chai n. The study also demonstrated that the soluble protein blocks Cvx and coll agen-induced platelet aggregation and that GPVI expression is restricted to megakaryocytes and platelets. Finally, human GPVI was mapped to chromosome 19, long arm, region 1, band 3 (19q13), in the same region as multiple mem bers of the Ig superfamily, This work offers the opportunity to explore the involvement of GPVI in thrombotic disease, to develop alternative antithro mbotic compounds, and to characterize the mechanism involved in GPVI geneti c deficiencies. (C) 2000 by The American Society of Hematology.