The complement protein C3 is a common denominator in the activation of the classical, alternative, and lectin pathways of the complement system. In addition, its interactions with several cell-surface receptors make it a key participant in phagocytic and immunoregulatory processes, while its interactions with proteins from foreign pathogens may provide a mechanism by which these microorganisms evade complement neutralization. To date, C3 is known to interact with at least 25 different proteins, including serum proteins, cell surface receptors and proteins of foreign origin. Elucidation of the molecular features related to these C3 associated interactions still requires further analysis of the C3 protein. The long-term goal of this proposal is to identify the structural determinants associated with various functions of this important macromolecule. The proposed study will involve a detailed structural and functional analysis of the interactions between the human C3 fragments C3(H2O), C3b, iC3b, C3c and C3dg, and the complement regulatory proteins, factor H and complement receptor type one (CR1) and to compare these interactions to those of the viral complement regulatory proteins VCP and SPICE with the same C3 fragments. Protein expression, isothermal titration calorimetry (ITC), and hydrogen exchange/mass spectrometry (HDX-MS) will be used to assess the molecular forces that impart specificity and recognition to the interactions between the host complement components and the host and viral regulatory proteins. The functional sites of the interacting molecules will be mapped using HDX-MS, computational methods, and site-directed mutagenesis. The proposed studies are designed to provide basic information on the structural features of C3-ligand interactions as they relate to complement functions. These studies should provide insight into how the virus's complement regulatory molecules help the virus evade complement attack and also assist in the design of specific inhibitors that may have important medical applications.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-III-F (01))
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Davidson, Wendy F
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University of Pennsylvania
Schools of Medicine
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Wang, HongBin; Ricklin, Daniel; Lambris, John D (2017) Complement-activation fragment C4a mediates effector functions by binding as untethered agonist to protease-activated receptors 1 and 4. Proc Natl Acad Sci U S A 114:10948-10953
Hajishengallis, G; Krauss, J L; Jotwani, R et al. (2017) Differential capacity for complement receptor-mediated immune evasion by Porphyromonas gingivalis depending on the type of innate leukocyte. Mol Oral Microbiol 32:154-165
Primikyri, Alexandra; Papanastasiou, Malvina; Sarigiannis, Yiannis et al. (2017) Method development and validation for the quantitation of the complement inhibitor Cp40 in human and cynomolgus monkey plasma by UPLC-ESI-MS. J Chromatogr B Analyt Technol Biomed Life Sci 1041-1042:19-26
Harder, Markus J; Kuhn, Nadine; Schrezenmeier, Hubert et al. (2017) Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation. Blood 129:970-980
Kajikawa, Tetsuhiro; Briones, Ruel A; Resuello, Ranillo R G et al. (2017) Safety and Efficacy of the Complement Inhibitor AMY-101 in a Natural Model of Periodontitis in Non-human Primates. Mol Ther Methods Clin Dev 6:207-215
Xue, Xiaoguang; Wu, Jin; Ricklin, Daniel et al. (2017) Regulator-dependent mechanisms of C3b processing by factor I allow differentiation of immune responses. Nat Struct Mol Biol 24:643-651
Gravastrand, Caroline; Hamad, Shamal; Fure, Hilde et al. (2017) Alginate microbeads are coagulation compatible, while alginate microcapsules activate coagulation secondary to complement or directly through FXII. Acta Biomater 58:158-167
Hajishengallis, George; Reis, Edimara S; Mastellos, Dimitrios C et al. (2017) Novel mechanisms and functions of complement. Nat Immunol 18:1288-1298
Papanastasiou, Malvina; Koutsogiannaki, Sophia; Sarigiannis, Yiannis et al. (2017) Structural Implications for the Formation and Function of the Complement Effector Protein iC3b. J Immunol 198:3326-3335
Schmidt, Christoph Q; Lambris, John D; Ricklin, Daniel (2016) Protection of host cells by complement regulators. Immunol Rev 274:152-171

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