The oxidoreductases of Neisseria meningitidis

Susannah Piek

    Research output: ThesisDoctoral Thesis

    282 Downloads (Pure)

    Abstract

    [Truncated] The Gram-negative bacterial outer membrane (OM), consisting of phospholipids, lipopolysaccharide (LPS) and proteins, forms a selective permeability barrier to the external environment and plays a key role in virulence. Disulfide bond (Dsb) proteins are required for the correct biogenesis of the protein components of the Gram-negative OM as they catalyse the formation of stabilising disulfide bonds. Recently, Dsb proteins have also been implicated in LPS biogenesis in E. coli, suggesting a much larger role of Dsb proteins in OM biogenesis and virulence of Gram-negative bacteria [7].
    While E. coli has been established as the model organism for periplasmic protein folding, this pathway is fundamentally different in N. meningitidis. E. coli contains a single DsbA enzyme (EcDsbA) which introduces disulfide bonds into a wide range of unrelated substrates, while N. meningitidis contains three DsbA enzymes, termed NmDsbA1, NmDsbA2 and NmDsbA3, which recognise a small cohort of specific proteins. This study aimed to identify features of these specialised meningococcal DsbA enzymes responsible for the differences in function. The crystal structures of the meningococcal DsbAs, NmDsbA1 [179] and NmDsbA3 (Appendix F (II)), were solved by our collaborator, Dr Martin Scanlon. In addition, our group proposed a model for the binding of substrates to EcDsbA. DsbA consists of two domains, the -domain inserted into a thioredoxin domain containing the active site, CXXC. The -domain is flanked by two flexible hinge regions, H1 and H2, and it was these residues which also interacted with the bound substrate in our structure model (Appendix F (I)).
    Original languageEnglish
    QualificationDoctor of Philosophy
    Publication statusUnpublished - 2012

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