PDBsum entry 2w81

Immune system

PDB id: 2w81

Contents

Protein chains

115 a.a. *

121 a.a. *

242 a.a. *

Waters ×424

* Residue conservation analysis

PDB id:

2w81

Name:

Immune system

Title:

Structure of a complex between neisseria meningitidis factor h binding protein and ccps 6-7 of human complement factor h

Structure:

Complement factor h. Chain: a, b, e. Fragment: ccps 6 and 7, residues 321-443. Synonym: h factor 1. Engineered: yes. Factor h binding protein. Chain: c, d, f. Fragment: full protein without signal sequence, residues 71-320. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Variant: his 402 form. Expressed in: escherichia coli. Expression_system_taxid: 469008. Neisseria meningitidis. Organism_taxid: 487.

Resolution:

2.35Å R-factor: 0.274 R-free: 0.283

Authors:

M.C.Schneider,B.E.Prosser,J.J.E.Caesar,E.Kugelberg,S.Li,Q.Zhang, S.Quoraishi,J.E.Lovett,J.E.Deane,R.B.Sim,P.Roversi,S.Johnson, C.M.Tang,S.M.Lea

Key ref:

M.C.Schneider et al. (2009). Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates. Nature, 458, 890-893. PubMed id: 19225461 DOI: 10.1038/nature07769

Date:

08-Jan-09 Release date: 03-Mar-09

Protein chain

P08603  (CFAH_HUMAN) -  Complement factor H from Homo sapiens

Seq: 1231 a.a.

Struc: 115 a.a.*

Protein chains

P08603  (CFAH_HUMAN) -  Complement factor H from Homo sapiens

Seq: 1231 a.a.

Struc: 121 a.a.*

Protein chains

Q9JXV4  (Q9JXV4_NEIMB) -  Factor H binding protein from Neisseria meningitidis serogroup B (strain ATCC BAA-335 / MC58)

Seq: 274 a.a.

Struc: 242 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1038/nature07769

Nature 458:890-893 (2009)

PubMed id: 19225461

Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates.

M.C.Schneider, B.E.Prosser, J.J.Caesar, E.Kugelberg, S.Li, Q.Zhang, S.Quoraishi, J.E.Lovett, J.E.Deane, R.B.Sim, P.Roversi, S.Johnson, C.M.Tang, S.M.Lea.

ABSTRACT

The complement system is an essential component of the innate and acquired immune system, and consists of a series of proteolytic cascades that are initiated by the presence of microorganisms. In health, activation of complement is precisely controlled through membrane-bound and soluble plasma-regulatory proteins including complement factor H (fH; ref. 2), a 155 kDa protein composed of 20 domains (termed complement control protein repeats). Many pathogens have evolved the ability to avoid immune-killing by recruiting host complement regulators and several pathogens have adapted to avoid complement-mediated killing by sequestering fH to their surface. Here we present the structure of a complement regulator in complex with its pathogen surface-protein ligand. This reveals how the important human pathogen Neisseria meningitidis subverts immune responses by mimicking the host, using protein instead of charged-carbohydrate chemistry to recruit the host complement regulator, fH. The structure also indicates the molecular basis of the host-specificity of the interaction between fH and the meningococcus, and informs attempts to develop novel therapeutics and vaccines.

Selected figure(s)

Figure 2.
Figure 2: Structure of fHbp and its complex with fH67. a, Two views of a cartoon representation of fHbp (residues 80–320). The cartoon is coloured according to the regions previously used to study fHbp (A region, yellow; B region, green; C region, cyan), illustrating the way in which these constructs do not reflect the overall architecture. b, Cartoon of the fHbp–fH67 complex with fHbp coloured as in a and fH67 in dark blue. Side chains from both proteins involved in forming salt bridges across the interaction surface are shown in red as ball-and-stick representations (zoomed and reoriented in inset box). c, Topology of fHbp and fH67 coloured as in b with the number of the residues involved in either H-bond or salt-bridge interactions between the proteins highlighted in red. The numbering scheme used throughout is as per Uniprot sequence Q9JXV4. This scheme is offset by +164 from the numbering used for the earlier NMR structure^11 (which was numbered from the start of their fragment) and by –65 from the scheme used in ref. 10 where numbering started from residue 1 of the mature protein without the signal sequence.

Figure 3.
Figure 3: Interference with fHbp binding of fH. a, Site-directed mutagenesis using Ala to substitute charged side-chains, shown by the structure to be involved in complex formation, abolishes binding to the wild-type form of their partner at concentrations around the wild-type K[d]. The black bar indicates the time period for which the fH analytes were injected (at 50 nM, 40 l min^-1) over the fHbp surfaces. b, Overlay of the fH-bound SOS (in gold as ball-and-stick and semi-transparent surface) from the structure of fH678 in complex with SOS^21 onto our fHbp–fH67 structure (coloured as in Fig. 2b). This demonstrates that the sites of SOS and fHbp binding overlap, suggesting that SOS could inhibit the interaction. c, Mimicry of GAG binding to fH via sulphate interactions (left panel: SOS, green carbons; fH, grey carbons) by charged side chain (Glu 304) of fHbp (right panel: fHbp, cyan carbons; fH, grey carbons). d, SPR demonstrates that SOS inhibits binding of fHbp to fH in the mM concentration range (fH678 injected at 4 nM, 40 l min^-1 in presence of varying amounts of SOS). Values show mean s.d., n = 3. e, Mapping of sites of amino acid differences in CCP6 of fH between human (UniProt P08603) and rhesus macaque (UniProt O19279). Residues which are altered shown in pink, space filling representation, with fHbp and fH67 shown as in Fig. 2b.

The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: Nature (2009, 458, 890-893) copyright 2009.

Figures were selected by an automated process.