4ZD3

Structure of a transglutaminase 2-specific autoantibody Fab fragment

Summary for 4ZD3

• Entry DOI: 10.2210/pdb4zd3/pdb
• Descriptor: 679-14-14E06 Fab fragment heavy chain, 679-14-14E06 Fab fragment light chain (3 entities in total)
• Functional Keywords: transglutaminase 2, antibody, fab fragment, celiac disease, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 47701.17

Authors

Chen, X.,Dalhus, B.,Hnida, K.,Iversen, R.,Sollid, L.M. (deposition date: 2015-04-16, release date: 2015-07-22, Last modification date: 2024-11-06)

Primary citation

Chen, X.,Hnida, K.,Graewert, M.A.,Andersen, J.T.,Iversen, R.,Tuukkanen, A.,Svergun, D.,Sollid, L.M.
Structural Basis for Antigen Recognition by Transglutaminase 2-specific Autoantibodies in Celiac Disease.
J.Biol.Chem., 290:21365-21375, 2015

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 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.

PubMed: 26160175
DOI: 10.1074/jbc.M115.669895

Experimental method

X-RAY DIFFRACTION (2.4 Å)