Structure and interactions of the proteins from the contact system

The contact system includes factor XII (FXII), FXI, prekallikrein (PK), and high-molecular-weight kininogen (HK), and has received increased interest as a potential target in immunothrombotic and inflammatory diseases. This system activates 2 distinct pathways, the intrinsic pathway of coagulation via cleavage of FIX, and inflammation via HK cleavage resulting in bradykinin (BK) generation. HK is central to the function of both arms of the system as a substrate for plasma kallikrein and critical cofactor, which forms interactions with cell receptors and activators. Both FXI and PK circulate in complex with HK and both can be cleaved by activated FXII. Reciprocal activation and continuous consumption of PK and FXII is a feature of the contact system. On endothelial cells, PK and FXII become activated but only in the presence of secreted receptor for the globular domain of C1q and Zn2+ ions. A second mechanism exists on endothelial cells whereby prolylcarboxypeptidase activates the PK-HK complex to generate BK in an FXII-independent manner. On platelets, FXI can be cleaved by thrombin, but only in the presence of secreted polyphosphate. This review explores the 3-dimensional structure of the contact factors and examines the molecular mechanisms underlying contact activation. We focus on conformational changes that expose cleavage sites and exosites in FXII, PK, and FXI. We also discuss contact factor protein-protein interactions, recognition of polyanions, and the role of HK and Zn2+ in contact system assembly.