8oxx
From Proteopedia
Transglutaminase 3 in complex with inhibitor Z-don and DH patient-derived Fab DH63-B02
Structural highlights
FunctionTGM3_HUMAN Catalyzes the calcium-dependent formation of isopeptide cross-links between glutamine and lysine residues in various proteins, as well as the conjugation of polyamines to proteins. Involved in the formation of the cornified envelope (CE), a specialized component consisting of covalent cross-links of proteins beneath the plasma membrane of terminally differentiated keratinocytes. Catalyzes small proline-rich proteins (SPRR1 and SPRR2) and LOR cross-linking to form small interchain oligomers, which are further cross-linked by TGM1 onto the growing CE scaffold (By similarity). In hair follicles, involved in cross-linking structural proteins to hardening the inner root sheath. Publication Abstract from PubMedTransglutaminase 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 beta-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 beta-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. Autoantibody binding and unique enzyme-substrate intermediate conformation of human transglutaminase 3.,Heggelund JE, Das S, Stamnaes J, Iversen R, Sollid LM Nat Commun. 2023 Oct 5;14(1):6216. doi: 10.1038/s41467-023-42004-z. PMID:37798283[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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