PDBsum entry 1dee

Immune system

PDB id: 1dee

Contents

Protein chains

214 a.a. *

223 a.a. *

51 a.a. *

54 a.a. *

Waters ×10

* Residue conservation analysis

References listed in PDB file

Key reference

Title

Crystal structure of a staphylococcus aureus protein a domain complexed with the FAB fragment of a human igm antibody: structural basis for recognition of b-Cell receptors and superantigen activity.

Authors

M.Graille, E.A.Stura, A.L.Corper, B.J.Sutton, M.J.Taussig, J.B.Charbonnier, G.J.Silverman.

Ref.

Proc Natl Acad Sci U S A, 2000, 97, 5399-5404. [DOI no: 10.1073/pnas.97.10.5399]

PubMed id

10805799

Abstract

Staphylococcus aureus produces a virulence factor, protein A (SpA), that contains five homologous Ig-binding domains. The interactions of SpA with the Fab region of membrane-anchored Igs can stimulate a large fraction of B cells, contributing to lymphocyte clonal selection. To understand the molecular basis for this activity, we have solved the crystal structure of the complex between domain D of SpA and the Fab fragment of a human IgM antibody to 2.7-A resolution. In the complex, helices II and III of domain D interact with the variable region of the Fab heavy chain (V(H)) through framework residues, without the involvement of the hypervariable regions implicated in antigen recognition. The contact residues are highly conserved in human V(H)3 antibodies but not in other families. The contact residues from domain D also are conserved among all SpA Ig-binding domains, suggesting that each could bind in a similar manner. Features of this interaction parallel those reported for staphylococcal enterotoxins that are superantigens for many T cells. The structural homology between Ig V(H) regions and the T-cell receptor V(beta) regions facilitates their comparison, and both types of interactions involve lymphocyte receptor surface remote from the antigen binding site. However, T-cell superantigens reportedly interact through hydrogen bonds with T-cell receptor V(beta) backbone atoms in a primary sequence-independent manner, whereas SpA relies on a sequence-restricted conformational binding with residue side chains, suggesting that this common bacterial pathogen has adopted distinct molecular recognition strategies for affecting large sets of B and T lymphocytes.

Figure 1.
Fig. 1. Schematic representation of the complex between SpA domain D and Fab 2A2 from a human IgM. (A) Side view showing SpA domain D (red) bound to the framework region of the Fab heavy chain (cyan). The V[L] domain, which is not involved in this interaction, is shown in dark blue. The CDR loops as defined by Chothia and Lesk (33) are highlighted in magenta. (B) Ribbon representation of the V[H] region of Fab showing the positions of the residues that interact with domain D. (C) Schematic diagram detailing the residues of SpA domain D and Fab 2A2 involved in the interaction. Kabat numbering is used for the V[H] residues (blue); domain D is numbered (in brown) with the convention used for SpA domains (34). Contact residues are identified if 20 Å2 or more of their surface are buried in the interface and if they make at least one van der Waals contact. All figures were generated by using MOLMOL (35).

Figure 2.
Fig. 2. Interactions of individual SpA domains. (A) Alignment of the amino acid sequences of the five SpA domains. Domain D residues involved in interaction with Fab 2A2 are highlighted in cyan. With the exception of Gln-32 (pink), there is no overlap between the residues involved in Fab interaction and those mediating Fc binding (2) (gray highlight). The engineered domain Z differs by the key mutation Gly-29 in Ala and does not bind Fab. The residues involved in the dimer of domain D observed in the asymmetric unit are indicated by red and green boxes. (B) Cross-linking of a V[H]3 Fab (cyan surface) and a Fc (gray surface) by a single domain of SpA (red ribbon). This model is based on the superposition of helix I and II of SpA domains in the Fab-domain D complex reported here and in the previously determined Fc -domain B complex (2) (rmsd of 0.73 Å for 140 backbone atoms). (C) Interface between domain D monomers. Schematic view of the interaction between the two domains D observed in the asymmetric unit, dom-D1 (red ribbon) and dom-D2 (green ribbon). Contact residues from both domains are shown in stick representation.