Dermatitis herpetiformis (DH), a skin manifestation of the gluten-sensitive condition celiac disease, is hallmarked by autoantibody production to transglutaminase 3 (TG3). TG3 is a calcium dependent enzyme that targets glutamine residues in polypeptides for either transamidation or deamidation modifications. A good substrate for TG3 is dietary gluten. TG3 has four domains (N-terminal, catalytic core and two C-terminal β-barrels: C1 and C2). Full catalytic activity requires both calcium binding and proteolytic cleavage between the catalytic core and the C1C2 domains.
We have solved the co-crystal structures of three different DH patient-derived autoantibodies in complex with TG3. One of these antibodies, termed DH63-A02, significantly enhances TG3 activity in in vitro assays1. Upon binding this antibody, TG3 undergoes a large conformational change as a β-sheet in the catalytic core moves and C1C2 detaches, leaving the active site fully accessible to gluten substrates.
These findings support a model where B cells expressing anti-TG3 antibodies as B-cell receptors (BCRs) bind and internalize TG3-gluten enzyme-substrate complexes. This facilitates gluten-antigen presentation, T-cell help and autoantibody production. Consequently, antibody-driven stabilization of TG3 in its active conformation enhances gluten presentation to T cells when expressed as BCRs, providing a structural mechanism for disease propagation in DH.