Barlow, Paul

Uhrin, Dusan

Hocking, Henry G.

2010-09-30T15:01:40Z

2010-09-30T15:01:40Z

2008-10

Factor H (FH) is a key regulator of the complement system, the principal molecular component of innate immunity in humans. The tight regulation of the alternative pathway (AP) of complement by FH occurs on host cells as well as in fluid phase. FH regulation of AP is achieved through its C3b.Bb-decay accelerating activity and cofactor activity for C3b proteolysis by factor I. This study presents evidence that the first three CCP modules, i.e. FH~1-3, constitute the minimal unit with cofactor activity for factor I. The work presented in this thesis describes the recombinant protein expression and NMR-derived structure determination of two overlapping pairs, FH~1-2 and FH~2-3, together with the use of these structures to build a model of the FH~1-3 structure. A structural comparison with other C3bengaging proteins (namely factor B, complement receptor type 1 and decay accelerating factor) is presented and used to devise hypotheses as to the respective roles of the three modules during an encounter with the convertase. This thesis further describes an investigation of the structural effects of two disease-associated sequence variants in the context of FH~1-2: namely the single nucleotide polymorphism V62I linked to age-related macular degeneration, and the R53H mutation linked to atypical haemolytic uraemic syndrome.

http://hdl.handle.net/1842/3785

en

The University of Edinburgh

Hocking, H. G., Herbert, A. P., Kavanagh, D., Soares, D. C., Ferreira, V. P., Pangburn, M. "Structure of the N-terminal Region of Complement Factor H and Conformational Implications of Disease-linked Sequence Variations" J. Biol. Chem. 283(14), 9475-9487

Factor H

complement regulation

NMR

Nuclear magnetic resonance

Structure of an active N-terminal fragment of human complement factor H

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy