Corticosteroid-binding globulin: structure-function implications from species differences.

Corticosteroid-binding globulin (CBG) transports glucocorticoids and progesterone in the blood and thereby modulates the tissue availability of these hormones. As a member of the serine protease inhibitor (SERPIN) family, CBG displays a reactive center loop (RCL) that is targeted by proteinases. Cle...

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Autores principales:	Bernd R Gardill, Michael R Vogl, Hai-Yan Lin, Geoffrey L Hammond, Yves A Muller
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ba66483af08845779325641d2766273f
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spelling	oai:doaj.org-article:ba66483af08845779325641d2766273f2021-11-18T08:03:37ZCorticosteroid-binding globulin: structure-function implications from species differences.1932-620310.1371/journal.pone.0052759https://doaj.org/article/ba66483af08845779325641d2766273f2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23300763/?tool=EBIhttps://doaj.org/toc/1932-6203Corticosteroid-binding globulin (CBG) transports glucocorticoids and progesterone in the blood and thereby modulates the tissue availability of these hormones. As a member of the serine protease inhibitor (SERPIN) family, CBG displays a reactive center loop (RCL) that is targeted by proteinases. Cleavage of the RCL is thought to trigger a SERPIN-typical stressed-to-relaxed (S-to-R) transition that leads to marked structural rearrangements and a reduced steroid-binding affinity. To characterize structure-function relationships in CBG we studied various conformational states of E. coli-produced rat and human CBG. In the 2.5 Å crystal structure of human CBG in complex with progesterone, the RCL is cleaved at a novel site that differs from the known human neutrophil elastase recognition site. Although the cleaved RCL segment is five residues longer than anticipated, it becomes an integral part of β-sheet A as a result of the S-to-R transition. The atomic interactions observed between progesterone and CBG explain the lower affinity of progesterone in comparison to corticosteroids. Surprisingly, CD measurements in combination with thermal unfolding experiments show that rat CBG fails to undergo an S-to-R transition upon proteolytic cleavage of the RCL hinting that the S-to-R transition observed in human CBG is not a prerequisite for CBG function in rat. This observation cautions against drawing general conclusions about molecular mechanisms by comparing and merging structural data from different species.Bernd R GardillMichael R VoglHai-Yan LinGeoffrey L HammondYves A MullerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 12, p e52759 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Bernd R Gardill Michael R Vogl Hai-Yan Lin Geoffrey L Hammond Yves A Muller Corticosteroid-binding globulin: structure-function implications from species differences.
description	Corticosteroid-binding globulin (CBG) transports glucocorticoids and progesterone in the blood and thereby modulates the tissue availability of these hormones. As a member of the serine protease inhibitor (SERPIN) family, CBG displays a reactive center loop (RCL) that is targeted by proteinases. Cleavage of the RCL is thought to trigger a SERPIN-typical stressed-to-relaxed (S-to-R) transition that leads to marked structural rearrangements and a reduced steroid-binding affinity. To characterize structure-function relationships in CBG we studied various conformational states of E. coli-produced rat and human CBG. In the 2.5 Å crystal structure of human CBG in complex with progesterone, the RCL is cleaved at a novel site that differs from the known human neutrophil elastase recognition site. Although the cleaved RCL segment is five residues longer than anticipated, it becomes an integral part of β-sheet A as a result of the S-to-R transition. The atomic interactions observed between progesterone and CBG explain the lower affinity of progesterone in comparison to corticosteroids. Surprisingly, CD measurements in combination with thermal unfolding experiments show that rat CBG fails to undergo an S-to-R transition upon proteolytic cleavage of the RCL hinting that the S-to-R transition observed in human CBG is not a prerequisite for CBG function in rat. This observation cautions against drawing general conclusions about molecular mechanisms by comparing and merging structural data from different species.
format	article
author	Bernd R Gardill Michael R Vogl Hai-Yan Lin Geoffrey L Hammond Yves A Muller
author_facet	Bernd R Gardill Michael R Vogl Hai-Yan Lin Geoffrey L Hammond Yves A Muller
author_sort	Bernd R Gardill
title	Corticosteroid-binding globulin: structure-function implications from species differences.
title_short	Corticosteroid-binding globulin: structure-function implications from species differences.
title_full	Corticosteroid-binding globulin: structure-function implications from species differences.
title_fullStr	Corticosteroid-binding globulin: structure-function implications from species differences.
title_full_unstemmed	Corticosteroid-binding globulin: structure-function implications from species differences.
title_sort	corticosteroid-binding globulin: structure-function implications from species differences.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/ba66483af08845779325641d2766273f
work_keys_str_mv	AT berndrgardill corticosteroidbindingglobulinstructurefunctionimplicationsfromspeciesdifferences AT michaelrvogl corticosteroidbindingglobulinstructurefunctionimplicationsfromspeciesdifferences AT haiyanlin corticosteroidbindingglobulinstructurefunctionimplicationsfromspeciesdifferences AT geoffreylhammond corticosteroidbindingglobulinstructurefunctionimplicationsfromspeciesdifferences AT yvesamuller corticosteroidbindingglobulinstructurefunctionimplicationsfromspeciesdifferences
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Corticosteroid-binding globulin: structure-function implications from species differences.

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