The Z mutation alters the global structural dynamics of α1-antitrypsin.

α1-Antitrypsin (α1AT) deficiency, the most common serpinopathy, results in both emphysema and liver disease. Over 90% of all clinical cases of α1AT deficiency are caused by the Z variant in which Glu342, located at the top of s5A, is replaced by a Lys which results in polymerization both in vivo and...

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Autores principales:	Victoria A Hughes, Robert Meklemburg, Stephen P Bottomley, Patrick L Wintrode
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1441956e44c84a3689847f3755838e6e
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spelling	oai:doaj.org-article:1441956e44c84a3689847f3755838e6e2021-11-25T06:02:14ZThe Z mutation alters the global structural dynamics of α1-antitrypsin.1932-620310.1371/journal.pone.0102617https://doaj.org/article/1441956e44c84a3689847f3755838e6e2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25181470/?tool=EBIhttps://doaj.org/toc/1932-6203α1-Antitrypsin (α1AT) deficiency, the most common serpinopathy, results in both emphysema and liver disease. Over 90% of all clinical cases of α1AT deficiency are caused by the Z variant in which Glu342, located at the top of s5A, is replaced by a Lys which results in polymerization both in vivo and in vitro. The Glu342Lys mutation removes a salt bridge and a hydrogen bond but does not effect the thermodynamic stability of Z α1AT compared to the wild type protein, M α1AT, and so it is unclear why Z α1AT has an increased polymerization propensity. We speculated that the loss of these interactions would make the native state of Z α1AT more dynamic than M α1AT and that this change renders the protein more polymerization prone. We have used hydrogen/deuterium exchange combined with mass spectrometry (HXMS) to determine the structural and dynamic differences between native Z and M α1AT to reveal the molecular basis of Z α1AT polymerization. Our HXMS data shows that the Z mutation significantly perturbs the region around the site of mutation. Strikingly the Z mutation also alters the dynamics of regions distant to the mutation such as the B, D and I helices and specific regions of each β-sheet. These changes in global dynamics may lead to an increase in the likelihood of Z α1AT sampling a polymerogenic structure thereby causing disease.Victoria A HughesRobert MeklemburgStephen P BottomleyPatrick L WintrodePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 9, p e102617 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Victoria A Hughes Robert Meklemburg Stephen P Bottomley Patrick L Wintrode The Z mutation alters the global structural dynamics of α1-antitrypsin.
description	α1-Antitrypsin (α1AT) deficiency, the most common serpinopathy, results in both emphysema and liver disease. Over 90% of all clinical cases of α1AT deficiency are caused by the Z variant in which Glu342, located at the top of s5A, is replaced by a Lys which results in polymerization both in vivo and in vitro. The Glu342Lys mutation removes a salt bridge and a hydrogen bond but does not effect the thermodynamic stability of Z α1AT compared to the wild type protein, M α1AT, and so it is unclear why Z α1AT has an increased polymerization propensity. We speculated that the loss of these interactions would make the native state of Z α1AT more dynamic than M α1AT and that this change renders the protein more polymerization prone. We have used hydrogen/deuterium exchange combined with mass spectrometry (HXMS) to determine the structural and dynamic differences between native Z and M α1AT to reveal the molecular basis of Z α1AT polymerization. Our HXMS data shows that the Z mutation significantly perturbs the region around the site of mutation. Strikingly the Z mutation also alters the dynamics of regions distant to the mutation such as the B, D and I helices and specific regions of each β-sheet. These changes in global dynamics may lead to an increase in the likelihood of Z α1AT sampling a polymerogenic structure thereby causing disease.
format	article
author	Victoria A Hughes Robert Meklemburg Stephen P Bottomley Patrick L Wintrode
author_facet	Victoria A Hughes Robert Meklemburg Stephen P Bottomley Patrick L Wintrode
author_sort	Victoria A Hughes
title	The Z mutation alters the global structural dynamics of α1-antitrypsin.
title_short	The Z mutation alters the global structural dynamics of α1-antitrypsin.
title_full	The Z mutation alters the global structural dynamics of α1-antitrypsin.
title_fullStr	The Z mutation alters the global structural dynamics of α1-antitrypsin.
title_full_unstemmed	The Z mutation alters the global structural dynamics of α1-antitrypsin.
title_sort	z mutation alters the global structural dynamics of α1-antitrypsin.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/1441956e44c84a3689847f3755838e6e
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The Z mutation alters the global structural dynamics of α1-antitrypsin.

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