Transglutaminase 2 undergoes a large conformational change upon activation.

Human transglutaminase 2 (TG2), a member of a large family of enzymes that catalyze protein crosslinking, plays an important role in the extracellular matrix biology of many tissues and is implicated in the gluten-induced pathogenesis of celiac sprue. Although vertebrate transglutaminases have been...

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Autores principales:	Daniel M Pinkas, Pavel Strop, Axel T Brunger, Chaitan Khosla
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2007
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1807f4db44564b6e8e5268aebe2b45fa
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spelling	oai:doaj.org-article:1807f4db44564b6e8e5268aebe2b45fa2021-11-25T05:33:32ZTransglutaminase 2 undergoes a large conformational change upon activation.1544-91731545-788510.1371/journal.pbio.0050327https://doaj.org/article/1807f4db44564b6e8e5268aebe2b45fa2007-12-01T00:00:00Zhttps://doi.org/10.1371/journal.pbio.0050327https://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Human transglutaminase 2 (TG2), a member of a large family of enzymes that catalyze protein crosslinking, plays an important role in the extracellular matrix biology of many tissues and is implicated in the gluten-induced pathogenesis of celiac sprue. Although vertebrate transglutaminases have been studied extensively, thus far all structurally characterized members of this family have been crystallized in conformations with inaccessible active sites. We have trapped human TG2 in complex with an inhibitor that mimics inflammatory gluten peptide substrates and have solved, at 2-A resolution, its x-ray crystal structure. The inhibitor stabilizes TG2 in an extended conformation that is dramatically different from earlier transglutaminase structures. The active site is exposed, revealing that catalysis takes place in a tunnel, bridged by two tryptophan residues that separate acyl-donor from acyl-acceptor and stabilize the tetrahedral reaction intermediates. Site-directed mutagenesis was used to investigate the acyl-acceptor side of the tunnel, yielding mutants with a marked increase in preference for hydrolysis over transamidation. By providing the ability to visualize this activated conformer, our results create a foundation for understanding the catalytic as well as the non-catalytic roles of TG2 in biology, and for dissecting the process by which the autoantibody response to TG2 is induced in celiac sprue patients.Daniel M PinkasPavel StropAxel T BrungerChaitan KhoslaPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 5, Iss 12, p e327 (2007)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Daniel M Pinkas Pavel Strop Axel T Brunger Chaitan Khosla Transglutaminase 2 undergoes a large conformational change upon activation.
description	Human transglutaminase 2 (TG2), a member of a large family of enzymes that catalyze protein crosslinking, plays an important role in the extracellular matrix biology of many tissues and is implicated in the gluten-induced pathogenesis of celiac sprue. Although vertebrate transglutaminases have been studied extensively, thus far all structurally characterized members of this family have been crystallized in conformations with inaccessible active sites. We have trapped human TG2 in complex with an inhibitor that mimics inflammatory gluten peptide substrates and have solved, at 2-A resolution, its x-ray crystal structure. The inhibitor stabilizes TG2 in an extended conformation that is dramatically different from earlier transglutaminase structures. The active site is exposed, revealing that catalysis takes place in a tunnel, bridged by two tryptophan residues that separate acyl-donor from acyl-acceptor and stabilize the tetrahedral reaction intermediates. Site-directed mutagenesis was used to investigate the acyl-acceptor side of the tunnel, yielding mutants with a marked increase in preference for hydrolysis over transamidation. By providing the ability to visualize this activated conformer, our results create a foundation for understanding the catalytic as well as the non-catalytic roles of TG2 in biology, and for dissecting the process by which the autoantibody response to TG2 is induced in celiac sprue patients.
format	article
author	Daniel M Pinkas Pavel Strop Axel T Brunger Chaitan Khosla
author_facet	Daniel M Pinkas Pavel Strop Axel T Brunger Chaitan Khosla
author_sort	Daniel M Pinkas
title	Transglutaminase 2 undergoes a large conformational change upon activation.
title_short	Transglutaminase 2 undergoes a large conformational change upon activation.
title_full	Transglutaminase 2 undergoes a large conformational change upon activation.
title_fullStr	Transglutaminase 2 undergoes a large conformational change upon activation.
title_full_unstemmed	Transglutaminase 2 undergoes a large conformational change upon activation.
title_sort	transglutaminase 2 undergoes a large conformational change upon activation.
publisher	Public Library of Science (PLoS)
publishDate	2007
url	https://doaj.org/article/1807f4db44564b6e8e5268aebe2b45fa
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Transglutaminase 2 undergoes a large conformational change upon activation.

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