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
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Publicado: Public Library of Science (PLoS) 2012
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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
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AT michaelrvogl corticosteroidbindingglobulinstructurefunctionimplicationsfromspeciesdifferences
AT haiyanlin corticosteroidbindingglobulinstructurefunctionimplicationsfromspeciesdifferences
AT geoffreylhammond corticosteroidbindingglobulinstructurefunctionimplicationsfromspeciesdifferences
AT yvesamuller corticosteroidbindingglobulinstructurefunctionimplicationsfromspeciesdifferences
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