Glycoprotein VI (GPVI) is a 63 kDa platelet/megakaryocyte-specific type I transmembrane glycoprotein of the immunoglobulin superfamily that is an important collagen receptor and initiator of platelet activation, aggregation and thrombin generation. GPVI is also a secondary receptor required for platelet spreading on laminin. Two splice variants exist; one is 17 aa shorter in the extracellular domain, while the other diverges at aa 260, creating an inactive monomeric and presumably secreted 681 aa protein. GPVI associates with the Fc receptor gamma-chain via charged aa in the transmembrane domains of GPVI (arginine) and the FcR-gamma (aspartic acid).
Collagen binding by the GPVI Ig-like domains initiates signaling through the FcR-gamma ITAM sequence. Dimerization of GPVI (2:2 with FcR-gamma) and N-glycosylation greatly enhances collagen binding. Type I and III collagens are strong thrombus-forming components in the vascular subendothelium and atherosclerotic plaques. GPVI initiates binding to fibrillar collagens under flow conditions, then activates integrin alpha2beta1 which binds collagen more tightly. GPVI deficiencies cause only a mild bleeding tendency, probably because integrin alpha2beta1 is able to minimally initiate collagen binding. Normal human GPVI concentration can vary widely and affect maximum thrombin generation. Engagement of GPVI by collagens or other agonists, including autoantibodies, causes calmodulin-regulated metalloproteinase cleavage of the 57 kDa ECD and depletes surface GPVI.