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Title: Bioinformatics studies on sequence, structure and functional relationships of proteins involved in the complement system
Author: Soares, Dinesh Christopher
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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Regulators of complement activation (RCA) ensure that a complement-mediated immune response is proportionate and targeted against infection. RCA proteins are characterised by numerous occurrences of a single module-type; the complement control protein (CCP) module. In this work, comprehensive bioinformatics analyses of sequence and structure of CCP modules was undertaken. Through extensive database and literature searches, CCP module sequences and structures were assembled and large-scale all-against-all sequence and structure comparisons performed, along with analysis of intermodular orientations for pairs of modules and larger fragments. Based upon optimal use of experimentally determined CCP module structures as templates, an automated large-scale protein structure comparative modelling procedure was implemented for a large set of CCP-module sequences. The models are publicly available online at “The CCP module model database”, which also serves as a comprehensive resource for information on CCP modules. The models are shown to serve as a rich vein of information for design of mutants, interpretation of phenotypic consequences of polymorphisms, and prediction of function. For example, the models proved useful for inferring the consequences of several disease-associated sequence variations of complement proteins, CR1, factor H, MCP; and another CCP-containing protein, SRPX2. Finally, homology models of C5 and C5b were created on the basis of the recent landmark publication of C3 and C3b structures. This exercise revealed the existence of a novel putative disulfide bond specific to C5. Additionally it helped revisit previous peptide and mutant-based studies and provided insight into the latter stages of complement assembly.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available