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Title | Structural Basis for Antigen Recognition by Transglutaminase 2-specific Autoantibodies in Celiac Disease. |
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Journal, issue, pages | J Biol Chem, Vol. 290, Issue 35, Page 21365-21375, Year 2015 |
Publish date | Aug 28, 2015 |
Authors | Xi Chen / Kathrin Hnida / Melissa Ann Graewert / Jan Terje Andersen / Rasmus Iversen / Anne Tuukkanen / Dmitri Svergun / Ludvig M Sollid / |
PubMed Abstract | Antibodies to the autoantigen transglutaminase 2 (TG2) are a hallmark of celiac disease. We have studied the interaction between TG2 and an anti-TG2 antibody (679-14-E06) derived from a single gut ...Antibodies to the autoantigen transglutaminase 2 (TG2) are a hallmark of celiac disease. We have studied the interaction between TG2 and an anti-TG2 antibody (679-14-E06) derived from a single gut IgA plasma cell of a celiac disease patient. The antibody recognizes one of four identified epitopes targeted by antibodies of plasma cells of the disease lesion. The binding interface was identified by small angle x-ray scattering, ab initio and rigid body modeling using the known crystal structure of TG2 and the crystal structure of the antibody Fab fragment, which was solved at 2.4 Å resolution. The result was confirmed by testing binding of the antibody to TG2 mutants by ELISA and surface plasmon resonance. TG2 residues Arg-116 and His-134 were identified to be critical for binding of 679-14-E06 as well as other epitope 1 antibodies. In contrast, antibodies directed toward the two other main epitopes (epitopes 2 and 3) were not affected by these mutations. Molecular dynamics simulations suggest interactions of 679-14-E06 with the N-terminal domain of TG2 via the CDR2 and CDR3 loops of the heavy chain and the CDR2 loop of the light chain. In addition there were contacts of the framework 3 region of the heavy chain with the catalytic domain of TG2. The results provide an explanation for the biased usage of certain heavy and light chain gene segments by epitope 1-specific antibodies in celiac disease. |
External links | J Biol Chem / PubMed:26160175 / PubMed Central |
Methods | SAS (X-ray synchrotron) / X-ray diffraction |
Resolution | 2.4 Å |
Structure data | SASDA28: SASDA38: SASDA48: PDB-4zd3: |
Chemicals | ChemComp-HOH: |
Source |
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Keywords | IMMUNE SYSTEM / transglutaminase 2 / antibody / Fab fragment / celiac disease |