TY - JOUR
T1 - Structure of human IgM rheumatoid factor Fab bound to its autoantigen IgG Fc reveals a novel topology of antibody-antigen interaction
AU - Corper, Adam L.
AU - Sohi, Maninder K.
AU - Bonagura, Vincent R.
AU - Steinitz, Michael
AU - Jefferis, Royston
AU - Feinstein, Arnold
AU - Beale, Dennis
AU - Taussig, Michael J.
AU - Sutton, Brian J.
PY - 1997/5
Y1 - 1997/5
N2 - Rheumatoid factors are the characteristic autoantibodies of rheumatoid arthritis, which bind to the Fc regions of IgG molecules. Here we report the crystal structure of the Fab fragment of a patient-derived IgM rheumatoid factor (RF-AN) complexed with human IgG4 Fc, at 3.2 Å resolution. This is the first structure of an autoantibody-autoantigen complex. The epitope recognized in IgG Fc includes the Cγ2/Cγ3 cleft region, and overlaps the binding sites of bacterial Fc-binding proteins. The antibody residues involved in autorecognition are all located at the edge of the conventional combining site surface, leaving much of the latter available, potentially, for recognition of a different antigen. Since an important contact residue is a somatic mutation, the structure implicates antigen-driven selection, following somatic mutation of germline genes, in the production of pathogenic rheumatoid factors.
AB - Rheumatoid factors are the characteristic autoantibodies of rheumatoid arthritis, which bind to the Fc regions of IgG molecules. Here we report the crystal structure of the Fab fragment of a patient-derived IgM rheumatoid factor (RF-AN) complexed with human IgG4 Fc, at 3.2 Å resolution. This is the first structure of an autoantibody-autoantigen complex. The epitope recognized in IgG Fc includes the Cγ2/Cγ3 cleft region, and overlaps the binding sites of bacterial Fc-binding proteins. The antibody residues involved in autorecognition are all located at the edge of the conventional combining site surface, leaving much of the latter available, potentially, for recognition of a different antigen. Since an important contact residue is a somatic mutation, the structure implicates antigen-driven selection, following somatic mutation of germline genes, in the production of pathogenic rheumatoid factors.
UR - http://www.scopus.com/inward/record.url?scp=0030938368&partnerID=8YFLogxK
U2 - 10.1038/nsb0597-374
DO - 10.1038/nsb0597-374
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C2 - 9145108
AN - SCOPUS:0030938368
SN - 1072-8368
VL - 4
SP - 374
EP - 381
JO - Nature Structural Biology
JF - Nature Structural Biology
IS - 5
ER -