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

Julie Elisabeth Heggelund (), Saykat Das, Jorunn Stamnaes, Rasmus Iversen and Ludvig M. Sollid ()
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Julie Elisabeth Heggelund: University of Oslo
Saykat Das: University of Oslo
Jorunn Stamnaes: University of Oslo
Rasmus Iversen: University of Oslo
Ludvig M. Sollid: University of Oslo

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42004-z

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