The complement system has emerged as a model of generation of biologically active products resulting from protein-protein interaction in plasma displaying marked structural versatility and proteolytic fragments generated from their precursor molecules. The significance of complement is, in part, emphasized by the fact that, the system is phylogenetically old. This application addresses three aspects of the relationship of structure to the function of the proteins of the complement system. 1. The phylogenetic evolution at DNA level of the regulatory proteins C4bp and H, utilizing data that indicates that lower vertebrates, including bony fish (sand bass), possess in their plasma a protein that serves the cofactor functions of H and C4bp in the degradation of human C4b and C3b. We will attempt to characterize the cDNA encoding for the sand bass protein and determine its nucleotide sequence. 2. The chemical definition of binding sites in C4b using monoclonal antibodies, enzymatically derived peptides, synthetic peptides, and polyclonal anti-peptide antibodies. In addition, the question of whether C4b exhibits a recognition function similar to that of C3b will be addressed using different activators, formation of the C4b2a enzyme and binding of the regulatory protein C4bp. 3. The elucidation of a unique pathway of activation of the alternative pathway that requires antibody, C1 and calcium ions, but is independent of C4 and C2.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI020067-09
Application #
3481088
Study Section
Experimental Immunology Study Section (EI)
Project Start
1982-09-15
Project End
1994-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
9
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Krushkal, J; Bat, O; Gigli, I (2000) Evolutionary relationships among proteins encoded by the regulator of complement activation gene cluster. Mol Biol Evol 17:1718-30
Krushkal, J; Kemper, C; Gigli, I (1998) Ancient origin of human complement factor H. J Mol Evol 47:625-30
Zipfel, P F; Kemper, C; Dahmen, A et al. (1996) Cloning and recombinant expression of a barred sand bass (Paralabrax nebulifer) cDNA. The encoded protein displays structural homology and immunological crossreactivity to human complement/cofactor related plasma proteins. Dev Comp Immunol 20:407-16
Schmitz, J; Zimmer, J P; Kluxen, B et al. (1995) Antibody-dependent complement-mediated cytotoxicity in sera from patients with HIV-1 infection is controlled by CD55 and CD59. J Clin Invest 96:1520-6
Dahmen, A; Kaidoh, T; Zipfel, P F et al. (1994) Cloning and characterization of a cDNA representing a putative complement-regulatory plasma protein from barred sand bass (Parablax neblifer). Biochem J 301 ( Pt 2):391-7
Barrett, K E; Yen, A; Bigby, T D et al. (1994) Inhibition of human peripheral blood lymphocyte function by protoporphyrin and longwave ultraviolet light. J Immunol 153:3286-94
Dovezenski, N; Billetta, R; Gigli, I (1992) Expression and localization of proteins of the complement system in human skin. J Clin Invest 90:2000-12
Tausk, F; Gigli, I (1990) The human C3b receptor: function and role in human diseases. J Invest Dermatol 94:141S-145S
Reed, S L; Gigli, I (1990) Lysis of complement-sensitive Entamoeba histolytica by activated terminal complement components. Initiation of complement activation by an extracellular neutral cysteine proteinase. J Clin Invest 86:1815-22
Kaidoh, T; Gigli, I (1989) Phylogeny of regulatory proteins of the complement system. Isolation and characterization of a C4b/C3b inhibitor and a cofactor from sand bass plasma. J Immunol 142:1605-13

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