Autoantibody binding and unique enzyme-substrate intermediate conformation of human transglutaminase 3

Nat Commun. 2023 Oct 5;14(1):6216. doi: 10.1038/s41467-023-42004-z.

Abstract

Transglutaminase 3 (TG3), the autoantigen of dermatitis herpetiformis (DH), is a calcium dependent enzyme that targets glutamine residues in polypeptides for either transamidation or deamidation modifications. To become catalytically active TG3 requires proteolytic cleavage between the core domain and two C-terminal β-barrels (C1C2). Here, we report four X-ray crystal structures representing inactive and active conformations of human TG3 in complex with a TG3-specific Fab fragment of a DH patient derived antibody. We demonstrate that cleaved TG3, upon binding of a substrate-mimicking inhibitor, undergoes a large conformational change as a β-sheet in the catalytic core domain moves and C1C2 detaches. The unique enzyme-substrate conformation of TG3 without C1C2 is recognized by DH autoantibodies. The findings support a model where B-cell receptors of TG3-specific B cells bind and internalize TG3-gluten enzyme-substrate complexes thereby facilitating gluten-antigen presentation, T-cell help and autoantibody production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantibodies
  • Celiac Disease*
  • Dermatitis Herpetiformis*
  • Glutens
  • Humans
  • Immunoglobulin A / metabolism
  • Transglutaminases

Substances

  • Autoantibodies
  • Transglutaminases
  • Immunoglobulin A
  • Glutens