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Title: Interactions of complement receptor type 2 with C3d and factor H with C3u
Author: Li, K.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2010
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Abstract:
Complement receptor type 2 (CR2, CD21) is a cell surface protein that links the innate and adaptive immune response through its binding to C3d, a cleavage fragment of the major complement component C3. Factor H (FH) is a major plasma protein that is the major regulator of the activity of C3b in the alternative pathway. FH binds to C3u, which is formed from C3 by hydrolysis, and C3u shows functional similarities to C3b. In this thesis, X-ray scattering, analytical ultracentrifugation and constrained modelling were used to determine solution structures and interactions of CR2 with C3d and FH with C3u. Structural studies reveal that the overall CR2 structure is unaffected by change in ionic strength or when C3d is bound to it. Unbound C3d exists in monomerdimer and monomer-trimer equilibria in low salt buffer, but as a monomer only in physiological buffer. The CR2-C3d interaction is not formed in physiological salt conditions, but was observed in low salt conditions. The solution structure and selfassociation of C3u were investigated. C3u underwent weak salt-dependent dimerisation, similar to that for C3d. Modelling showed that the functionally-important TED/CUB domains in the C3d part of C3u were extended away from the rest of the C3u structure. This TED/CUB conformation is intermediate between those of C3 and C3b. C3u and FH were observed to interact as 1:1 and 2:1 complexes in a salt-dependent manner. The modelling of the interaction showed that no major conformational changes occurred in C3u or FH, and suggested that C3u binds separately to FH at two independent sites. These results provide new insights in the activation of C3 and the complement regulatory activity of CR2 and FH.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.565128  DOI: Not available
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