COMPLEMENT RECEPTOR ONE (CR1)--STRUCTURE/FUNCTION

点击翻译按钮获取中文摘要

The complement system is an important part of the host's innate and acquired immune defense system: it serves in the identification and elimination of microorganisms, immune complexes and damaged tissue. Complement can also cause profound tissue damage in cases of autoimmunity, immune complex deposition, reperfusion injury, and xenograft rejection. Presently, there is no therapeutic agent for the inhibition of complement. Complement activation is controlled by the Regulators of Complement Activation (RCA) protein family. The most versatile member of this family is Complement Receptor 1 (CR1, CD35): CR1 on red blood cells mediates adherence and delivery of immune complexes to the fixed phagocytic system while CR1 on leukocytes promotes adherence and endocytosis. CR1 also mediates entry of certain C3b-coated pathogens into lymphocytes and RBCs, thus contributing to the infectious process. Recently, a soluble CR1 form has been shown in several animal models to be an inhibitor of complement-related tissue injury. CR1 interacts with several components of the complement activation pathways including C3b, C4b, and the C3 and C5 convertases. The long-term objectives of this application are to understand the molecular basis of these interactions and their role in CR1 function, and to design new therapeutic tools for complement regulation. Studies are proposed with the following specific aims: 1) Elucidate the structure of the CR1 active sites and design small CR1 analogs valuable for therapeutic applications. 2) Understand the mechanism of CR1 interactions with C3b/C4b and the convertases. 3) Determine how the biochemical properties of CR1 direct its cell surface function. The experimental approach would utilize site-directed mutagenesis of the CR1 active and subsequent in vitro assays with cell surface and fluid phase CR1 forms to elucidate key structure/function relationships, to define the contributions of each active region to biolgical function, and to produce small CR1 analogs of therapeutic potential.