gClq-R/p33: Structure Function and Role on Inflammation

The receptor for the globular heads of C1q, gC1q-R/p33, is a ubiquitously expressed cellular protein and comprises of three identical chains of -33 kDa. Although the primary destination is the mitochondria, it has a multi-compartmental distribution including its expression on the cell surface of endothelial cells and platelets. It is the cell -surface function that is the focus of this proposal. gC1q-R was initially identified as a receptor for C1q, but we have also shown binding to other biologically important ligands including high molecular weight kininogen (HK) and factor XII (FXII). Substantial experimental evidence supports the concept that gC1q-R plays an important role in the inflammatory process especially at sites of vascular injury where gC1 q-R expressing endothelial cells, platelets and macrophages are at the center of the process. The present proposal is designed to dissect the structure-function relationships of gC1q-R by focusing primarily on its binding to the cell surface and three of its specific ligands ¿C1q, HK and FXII. These ligands are not only critical in the initiation of the classical pathway of complement and contact activation; we propose they also play a major role at sites of inflammation by directly or indirectly enhancing the inflammatory process. The key aims are: 1) analysis of the role of structural domains of the molecule in its binding to cell surfaces and to major physiological ligands; 2) its role in inflammation, by assessing its regulatory and/or initiatory functions on the complement and contact activation systems (e.g. generation of potent vasoactive peptides like bradykinin); and 3) its role as a signaling agent in response to C1q, and perhaps other ligands, in endothelial cells, leading to generation of proinflammatory molecules. Understanding the function of gC1q-R is of biologic importance because it is a novel regulatory protein involved not only in the complement and kinin-generating systems, but also possibly the acquired or adaptive immune systems as well.