Translational mini-review series on complement factor H: structural and functional correlations for factor H

Abstract

The 155-kDa glycoprotein, complement factor H (CFH), is a regulator of complement activation that is abundant in human plasma. Three-dimensional structures of over half the 20 complement control protein (CCP) modules in CFH have been solved in the context of single-, double- and triple-module segments. Proven binding sites for C3b occupy the N and C termini of this elongated molecule and may be brought together by a bend in CFH mediated by its central CCP modules. The C-terminal CCP 20 is key to the ability of the molecule to adhere to polyanionic markers on self-surfaces where CFH acts to regulate amplification of the alternative pathway of complement. The surface patch on CCP 20 that binds to model glycosaminoglycans has been mapped using nuclear magnetic resonance (NMR), as has a second glycosaminoglycan-binding patch on CCP 7. These patches include many of the residue positions at which sequence variations have been linked to three complement-mediated disorders: dense deposit disease, age-related macular degeneration and atypical haemolytic uraemic syndrome. In one plausible model, CCP 20 anchors CFH to self-surfaces via a C3b/polyanion composite binding site, CCP 7 acts as a 'proof-reader' to help discriminate self- from non-self patterns of sulphation, and CCPs 1-4 disrupt C3/C5 convertase formation and stability.

Fig. 1

Multiple sequence alignment of 20 short consensus repeats in sequence of complement factor H (CFH). One-letter codes used throughout; invariant Cys residues and almost invariant Trp residue are highlighted. Arrows indicate other well-conserved residues. Each short consensus repeat (SCR) probably folds into a complement control protein (CCP) module; horizontal lines indicate disulphides within CCP module.

Fig. 2

Cartoon showing three-dimensional structure of the complement control protein (CCP) module pair, complement factor H (CFH) 19–20. Cys side-chains (green and orange) drawn [PyMol (Warren L. DeLano, ‘The PyMOL Molecular Graphics System’, DeLano Scientific LLC, San Carlos, CA, USA. http://www.pymol.org)] in space-fill representation; the three Trp side-chains (red) present are drawn in stick representation. Module 19 is typical of CCP modules; CCP 20 (lacking the consensus Trp) is less elongated than CCP 19.

Fig. 3

Summary of module-deletion/ truncations of complement factor H (CFH). Complement control protein (CCP) modules are shown as ovals within a cartoon-type representation of each deletion/truncation mutant. The black triangles indicate non-native linker lengths in one mutant. ‘CA’ written alongside indicates it has co-factor activity; similarly ‘H’, ‘C3b’, ‘C3c’, etc. indicate the mutant protein has binding affinity for heparin-affinity resin, C3b, C3c, etc. (ESC3b signifies sheep erythrocyte-bound C3b, as opposed to fluid-phase or chemically immobilized C3b); ‘PSE’: protects sheep erythrocytes from complement-mediated lysis. A strike-through means a particular activity was investigated but found not to be measurable; lower-case letters signify substantial reduction in measured activity; SFTL, the four residues specific to the C-terminus of CFH-like 1; ‘rr’, non-native N-terminal sequence containing two Arg residues. Superscripts refer to cited works as follows: A, Alsenz et al. [31,32]; G, Gordon et al. [34]; K, Kuhn [35]; J, Jokiranta et al. [36]; O, Ormsby et al. [37]; B, Blackmore et al. [38,39]; H, Herbert et al. [27]; HW, Hellwage et al. [40]; SP, Sharma and Pangburn [41]; and P, Pangburn [42].

Fig. 4

Amino acid residue positions of mutations listed in Table 1 within the structure of complement factor H (CFH) 19, 20. The structure of CFH 19, 20 is drawn as a cartoon in PyMol (see legend to Fig. 2). Mutated side-chains are labelled (and in parentheses if they are likely to be structurally critical) and drawn and their exposed surfaces are rendered (dark blue if they are positively charged, otherwise cyan). Underlining indicates that mutations in the residue concerned are linked to atypical haemolytic uraemic syndrome. The effect on function − where measured − is indicated by symbols (see key), except for residues likely to be critical for structural integrity.