The roles of helix I and strand 5A in the folding, function and misfolding of α1-antitrypsin.

α(1)-Antitrypsin, the archetypal member of the serpin superfamily, is a metastable protein prone to polymerization when exposed to stressors such as elevated temperature, low denaturant concentrations or through the presence of deleterious mutations which, in a physiological context, are often assoc...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Anja S Knaupp, Shani Keleher, Li Yang, Weiwen Dai, Stephen P Bottomley, Mary C Pearce
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/32cd3d06b9dd40a6a3c701ad211ce205
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:32cd3d06b9dd40a6a3c701ad211ce205
record_format	dspace
spelling	oai:doaj.org-article:32cd3d06b9dd40a6a3c701ad211ce2052021-11-18T07:59:41ZThe roles of helix I and strand 5A in the folding, function and misfolding of α1-antitrypsin.1932-620310.1371/journal.pone.0054766https://doaj.org/article/32cd3d06b9dd40a6a3c701ad211ce2052013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23382962/?tool=EBIhttps://doaj.org/toc/1932-6203α(1)-Antitrypsin, the archetypal member of the serpin superfamily, is a metastable protein prone to polymerization when exposed to stressors such as elevated temperature, low denaturant concentrations or through the presence of deleterious mutations which, in a physiological context, are often associated with disease. Experimental evidence suggests that α(1)-Antitrypsin can polymerize via several alternative mechanisms in vitro. In these polymerization mechanisms different parts of the molecule are proposed to undergo conformational change. Both strand 5 and helix I are proposed to adopt different conformations when forming the various polymers, and possess a number of highly conserved residues however their role in the folding and misfolding of α(1)-Antitrypsin has never been examined. We have therefore created a range of α(1)Antitypsin variants in order to explore the role of these conserved residues in serpin folding, misfolding, stability and function. Our data suggest that key residues in helix I mediate efficient folding from the folding intermediate and residues in strand 5A ensure native state stability in order to prevent misfolding. Additionally, our data indicate that helix I is involved in the inhibitory process and that both structural elements undergo differing conformational rearrangements during unfolding and misfolding. These findings suggest that the ability of α(1)-Antitrypsin to adopt different types of polymers under different denaturing conditions may be due to subtle conformational differences in the transiently populated structures adopted prior to the I and M* states.Anja S KnauppShani KeleherLi YangWeiwen DaiStephen P BottomleyMary C PearcePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 1, p e54766 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anja S Knaupp Shani Keleher Li Yang Weiwen Dai Stephen P Bottomley Mary C Pearce The roles of helix I and strand 5A in the folding, function and misfolding of α1-antitrypsin.
description	α(1)-Antitrypsin, the archetypal member of the serpin superfamily, is a metastable protein prone to polymerization when exposed to stressors such as elevated temperature, low denaturant concentrations or through the presence of deleterious mutations which, in a physiological context, are often associated with disease. Experimental evidence suggests that α(1)-Antitrypsin can polymerize via several alternative mechanisms in vitro. In these polymerization mechanisms different parts of the molecule are proposed to undergo conformational change. Both strand 5 and helix I are proposed to adopt different conformations when forming the various polymers, and possess a number of highly conserved residues however their role in the folding and misfolding of α(1)-Antitrypsin has never been examined. We have therefore created a range of α(1)Antitypsin variants in order to explore the role of these conserved residues in serpin folding, misfolding, stability and function. Our data suggest that key residues in helix I mediate efficient folding from the folding intermediate and residues in strand 5A ensure native state stability in order to prevent misfolding. Additionally, our data indicate that helix I is involved in the inhibitory process and that both structural elements undergo differing conformational rearrangements during unfolding and misfolding. These findings suggest that the ability of α(1)-Antitrypsin to adopt different types of polymers under different denaturing conditions may be due to subtle conformational differences in the transiently populated structures adopted prior to the I and M* states.
format	article
author	Anja S Knaupp Shani Keleher Li Yang Weiwen Dai Stephen P Bottomley Mary C Pearce
author_facet	Anja S Knaupp Shani Keleher Li Yang Weiwen Dai Stephen P Bottomley Mary C Pearce
author_sort	Anja S Knaupp
title	The roles of helix I and strand 5A in the folding, function and misfolding of α1-antitrypsin.
title_short	The roles of helix I and strand 5A in the folding, function and misfolding of α1-antitrypsin.
title_full	The roles of helix I and strand 5A in the folding, function and misfolding of α1-antitrypsin.
title_fullStr	The roles of helix I and strand 5A in the folding, function and misfolding of α1-antitrypsin.
title_full_unstemmed	The roles of helix I and strand 5A in the folding, function and misfolding of α1-antitrypsin.
title_sort	roles of helix i and strand 5a in the folding, function and misfolding of α1-antitrypsin.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/32cd3d06b9dd40a6a3c701ad211ce205
work_keys_str_mv	AT anjasknaupp therolesofhelixiandstrand5ainthefoldingfunctionandmisfoldingofa1antitrypsin AT shanikeleher therolesofhelixiandstrand5ainthefoldingfunctionandmisfoldingofa1antitrypsin AT liyang therolesofhelixiandstrand5ainthefoldingfunctionandmisfoldingofa1antitrypsin AT weiwendai therolesofhelixiandstrand5ainthefoldingfunctionandmisfoldingofa1antitrypsin AT stephenpbottomley therolesofhelixiandstrand5ainthefoldingfunctionandmisfoldingofa1antitrypsin AT marycpearce therolesofhelixiandstrand5ainthefoldingfunctionandmisfoldingofa1antitrypsin AT anjasknaupp rolesofhelixiandstrand5ainthefoldingfunctionandmisfoldingofa1antitrypsin AT shanikeleher rolesofhelixiandstrand5ainthefoldingfunctionandmisfoldingofa1antitrypsin AT liyang rolesofhelixiandstrand5ainthefoldingfunctionandmisfoldingofa1antitrypsin AT weiwendai rolesofhelixiandstrand5ainthefoldingfunctionandmisfoldingofa1antitrypsin AT stephenpbottomley rolesofhelixiandstrand5ainthefoldingfunctionandmisfoldingofa1antitrypsin AT marycpearce rolesofhelixiandstrand5ainthefoldingfunctionandmisfoldingofa1antitrypsin
_version_	1718422656160628736

The roles of helix I and strand 5A in the folding, function and misfolding of α1-antitrypsin.

Ejemplares similares