TY - JOUR
T1 - Crystal Structure of a Human Autoimmune Complex between IgM Rheumatoid Factor RF61 and IgG1 Fc Reveals a Novel Epitope and Evidence for Affinity Maturation
AU - Duquerroy, Stephane
AU - Stura, Enrico A.
AU - Bressanelli, Stéphane
AU - Fabiane, Stella M.
AU - Vaney, Marie C.
AU - Beale, Dennis
AU - Hamon, Maureen
AU - Casali, Paolo
AU - Rey, Felix A.
AU - Sutton, Brian J.
AU - Taussig, Michael J.
N1 - Funding Information:
This work was supported by NIH Grants AR 40908, AI 45011, and AI 60573 to PC. BJS, MJT and SMF thank the Biotechnology and Biological Sciences Research Council (BBSRC, UK) and the Arthritis Research Campaign (UK) for support and Susanne Bell for expert technical assistance. We also thank Helena Browne (Department of Pathology, University of Cambridge) for preparation of the gD–Fc construct.
PY - 2007/5/18
Y1 - 2007/5/18
N2 - Rheumatoid factors (RF) are autoantibodies that recognize epitopes in the Fc region of immunoglobulin (Ig) G and that correlate with the clinical severity of rheumatoid arthritis (RA). Here we report the X-ray crystallographic structure, at 3 Å resolution, of a complex between the Fc region of human IgG1 and the Fab fragment of a monoclonal IgM RF (RF61), derived from an RA patient and with a relatively high affinity for IgG Fc. In the complex, two Fab fragments bind to each Fc at epitopes close to the C terminus, and each epitope comprises residues from both Cγ3 domains. A central role in the unusually hydrophilic epitope is played by the side-chain of Arg355, accounting for the subclass specificity of RF61, which recognizes IgG1,- 2, and - 3 in preference to IgG4, in which the corresponding residue is Gln355. Compared with a previously determined complex of a lower affinity RF (RF-AN) bound to IgG4 Fc, in which only residues at the very edge of the antibody combining site were involved in binding, the epitope bound by RF61 is centered in classic fashion on the axis of the VH:VL β-barrel. The complementarity determining region-H3 loop plays a key role, forming a pocket in which Arg355 is bound by two salt-bridges. The antibody contacts also involve two somatically mutated VH residues, reinforcing the suggestion of a process of antigen-driven maturation and selection for IgG Fc during the generation of this RF autoantibody.
AB - Rheumatoid factors (RF) are autoantibodies that recognize epitopes in the Fc region of immunoglobulin (Ig) G and that correlate with the clinical severity of rheumatoid arthritis (RA). Here we report the X-ray crystallographic structure, at 3 Å resolution, of a complex between the Fc region of human IgG1 and the Fab fragment of a monoclonal IgM RF (RF61), derived from an RA patient and with a relatively high affinity for IgG Fc. In the complex, two Fab fragments bind to each Fc at epitopes close to the C terminus, and each epitope comprises residues from both Cγ3 domains. A central role in the unusually hydrophilic epitope is played by the side-chain of Arg355, accounting for the subclass specificity of RF61, which recognizes IgG1,- 2, and - 3 in preference to IgG4, in which the corresponding residue is Gln355. Compared with a previously determined complex of a lower affinity RF (RF-AN) bound to IgG4 Fc, in which only residues at the very edge of the antibody combining site were involved in binding, the epitope bound by RF61 is centered in classic fashion on the axis of the VH:VL β-barrel. The complementarity determining region-H3 loop plays a key role, forming a pocket in which Arg355 is bound by two salt-bridges. The antibody contacts also involve two somatically mutated VH residues, reinforcing the suggestion of a process of antigen-driven maturation and selection for IgG Fc during the generation of this RF autoantibody.
KW - X-ray crystallography
KW - autoantibody
KW - autoantigen
KW - autoimmunity
KW - rheumatoid factor
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U2 - 10.1016/j.jmb.2007.02.085
DO - 10.1016/j.jmb.2007.02.085
M3 - Article
C2 - 17395205
AN - SCOPUS:34247246737
SN - 0022-2836
VL - 368
SP - 1321
EP - 1331
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 5
ER -