PDBsum entry 1fhc

C-terminal domains of factor h

PDB id: 1fhc

Contents

Protein chain

127 a.a.

References listed in PDB file

Key reference

Title

Complement c3b/c3d and cell surface polyanions are recognized by overlapping binding sites on the most carboxyl-Terminal domain of complement factor h.

Authors

J.Hellwage, T.S.Jokiranta, M.A.Friese, T.U.Wolk, E.Kampen, P.F.Zipfel, S.Meri.

Ref.

J Immunol, 2002, 169, 6935-6944.

PubMed id

12471127

Abstract

Factor H (FH) is a potent suppressor of the alternative pathway of C in plasma and when bound to sialic acid- or glycosaminoglycan-rich surfaces. Of the three interaction sites on FH for C3b, one interacts with the C3d part of C3b. In this study, we generated recombinant constructs of FH and FH-related proteins (FHR) to define the sites required for binding to C3d. In FH, the C3d-binding site was localized by surface plasmon resonance analysis to the most C-terminal short consensus repeat domain (SCR) 20. To identify amino acids of FH involved in binding to C3d and heparin, we compared the sequences of FH and FHRs and constructed a homology-based molecular model of SCR19-20 of FH. Subsequently, we created an SCR15-20 mutant with substitutions in five amino acids that were predicted to be involved in the binding interactions. These mutations reduced binding of the SCR15-20 construct to both C3b/C3d and heparin. Binding of the wild-type SCR15-20, but not the residual binding of the mutated SCR15-20, to C3d was inhibited by heparin. This indicates that the heparin- and C3d-binding sites are overlapping. Our results suggest that a region in the most C-terminal domain of FH is involved in target recognition by binding to C3b and surface polyanions. Mutations in this region, as recently reported in patients with familial hemolytic uremic syndrome, may lead to indiscriminatory C attack against self cells.

Secondary reference #1

Title

X-Ray crystal structure of c3d: a c3 fragment and ligand for complement receptor 2.

Authors

B.Nagar, R.G.Jones, R.J.Diefenbach, D.E.Isenman, J.M.Rini.

Ref.

Science, 1998, 280, 1277-1281. [DOI no: 10.1126/science.280.5367.1277]

PubMed id

9596584

Figure 2.
Fig. 2. Sequence conservation of C3d. (A) Multiple sequence alignment of selected species of C3d and human C4d (B isotype) (21). Residues shaded in yellow are at least 90% buried in the^ C3d structure, and those shaded in red are residues composing the contiguous surface patch labeled in (B). Numbers correspond^ to the degree of conservation in C3d sequences only: 0 (not conserved) to A (highly conserved), as determined by the program AMAS (32). In human C4d, approximately 75% of the core residues, as well as the putative domain interface residues, are highly conserved^ [a conservation index (cons. index) of 7 or higher when included^ in the AMAS calculation], which suggests that it will adopt a^ similar fold and possess the analogous domain interface. The helical segments in human C3d are indicated by blue cylinders. [The figure^ was prepared with ALSCRIPT (35).] (B) Mapping of residue^ conservation as determined in (A) onto the surface of C3d; white^ (not conserved) to progressively darker red (highly conserved). [The figure was prepared with GRASP (36).] The conserved patch includes most of the surface apolar residues shown in Fig. 1C.

Figure 3.
Fig. 3. Stereo view of an electrostatic surface rendition of C3d, showing the acidic pocket on the concave end of the molecule. Acidic^ and basic residues are colored red and blue, respectively. Labeled^ are the surface-exposed residues that form the pocket. The contour level is at ±10 kT.

The above figures are reproduced from the cited reference with permission from the AAAs

Secondary reference #2

Title

Solution structure of a pair of complement modules by nuclear magnetic resonance.

Authors

P.N.Barlow, A.Steinkasserer, D.G.Norman, B.Kieffer, A.P.Wiles, R.B.Sim, I.D.Campbell.

Ref.

J Mol Biol, 1993, 232, 268-284.

PubMed id

8331663