Smith, Kathryn Frances; (1992) Structural investigations of the components of the complement cascade. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The complement cascade is a multi-component protein system found in plasma and plays an important role in immune defence. The molecular structures of five proteins were studied using a combination of neutron and X-ray small- angle solution scattering and secondary structure prediction techniques. α1-antitrypsin is the best characterized member of the serpin superfamily. It was shown to have a moderately elongated structure. Models of native and reactive-centre cleaved α1-antitrypsin were created based on the crystal coordinates of the cleaved protein. Since these were very similar, the gross conformational change between the two structures is minor. C1 inhibitor controls the activation of the classical pathway. It consists of a serpin domain and a highly glycosylated N-terminal domain. The structure of the serpin domain was based upon the crystal structure of α1-antitrypsin. The N-terminal domain was modelled as a highly elongated structure with extended carbohydrates. The activation of C5 initiates the formation of the membrane attack complex. Solution scattering showed that this had an elongated structure and was similar to the homologous proteins C3 and C4. Properdin is a regulatory protein of the alternative pathway. The properdin trimer was successfully modelled as a triangle of sides 26 nm in agreement with published electron micrographs. Monomeric properdin contains 6 thrombospondin repeats (TSR). Sequence alignments and secondary structure predictions of the TSR showed this to be comprised of two β-turn regions and one β-strand region. C9 is the most abundant member of the membrane attack complex. It consists of four domains: thrombospondin repeat (TSR), low density lipoprotein receptor (LDLr), perforin- like region (PLR) and an epidermal growth factor-like (EGF) domain. Again, solution scattering experiments showed C9 was elongated. Models for C9 suggest that the domains are arranged in a V shape with each arm of length 11.1 nm and inter-arm angle of 10°. A total of 74 LDLr, 10 PLR and 99 EGF sequences were aligned and their secondary structures predicted. The LDLr and EGF domains were found to consist of β-strand and β-turn conformations whilst the PLR was predominantly α-helix.

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