Our-long term objective has been to study the properties of C3, C4, and C5 that are related to their structural integrity and functionality. These proteins are components of the complement system, whose apparent main function is to help defend the human body against bacteria, viruses, yeast and foreign particles or substances. All three proteins have to be activated and fragmented to fulfill a variety of their physiological functions. Most of the fragments have the capacity to trigger cellular responses, some may participate even in an immune regulation. An additional stability to functional forms of C3, C4, and C5, or their fragments, is being conferred by disulfide bonds.
The specific aims of this project are: (1) To demonstrate the effect of distribution of disulfide linkages on conformation of the domains of C3 and C4, and to localize interchain, inter- and intradomains linkages in C3, C4, and C5. Determination of disulfide-bonding patterns will allow to understand the spacial arrangements within the polypeptide chains, and should provide another evidence for the importance of disulfide bonds for the structural and functional integrity in homologous proteins. The study of the interaction of highly cross- linked domains, and other domains, with physiological ligands will be attempted. (2) To elucidate the fragmentation pathway of the fluid-phase C3b, the activated form of C3. The physiologically relevant cleavage products generated in the absence of acceptor surfaces will be isolated by immunoaffinity chromatography and characterized by SDS-PAGE and by N-terminal sequence analysis. We propose to identify the enzyme responsible for the cleavage of the fluid-phase iC3b into C3c and C3d-containing fragments. Biological activities of the fluid-phase fragments, specifically those of C3d,g dimer and C3c, will be investigated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI019319-05
Application #
3128689
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1983-07-01
Project End
1991-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Aronov, A M; Munagala, N R; Kuntz, I D et al. (2001) Virtual screening of combinatorial libraries across a gene family: in search of inhibitors of Giardia lamblia guanine phosphoribosyltransferase. Antimicrob Agents Chemother 45:2571-6
Aronov, A M; Munagala, N R; Ortiz De Montellano, P R et al. (2000) Rational design of selective submicromolar inhibitors of Tritrichomonas foetus hypoxanthine-guanine-xanthine phosphoribosyltransferase. Biochemistry 39:4684-91
Lin, Y S; Hlady, V; Janatova, J (1992) Adsorption of complement proteins on surfaces with a hydrophobicity gradient. Biomaterials 13:497-504
Cheung, A K; Parker, C J; Janatova, J et al. (1992) Modulation of complement activation on hemodialysis membranes by immobilized heparin. J Am Soc Nephrol 2:1328-37
Janatova, J; Cheung, A K; Parker, C J (1991) Biomedical polymers differ in their capacity to activate complement. Complement Inflamm 8:61-9
Cheung, A K; Parker, C J; Wilcox, L A et al. (1990) Activation of complement by hemodialysis membranes: polyacrylonitrile binds more C3a than cuprophan. Kidney Int 37:1055-9
Cheung, A K; Parker, C J; Janatova, J (1989) Analysis of the complement C3 fragments associated with hemodialysis membranes. Kidney Int 35:576-88
Cheung, A K; Parker, C J; Wilcox, L et al. (1989) Activation of the alternative pathway of complement by cellulosic hemodialysis membranes. Kidney Int 36:257-65
Janatova, J (1988) C3, C5 components and C3a, C4a, and C5a fragments of the complement system. Methods Enzymol 162:579-625
Janatova, J (1986) Detection of disulphide bonds and localization of interchain linkages in the third (C3) and the fourth (C4) components of human complement. Biochem J 233:819-25

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