Inherent flexibility of CLIC6 revealed by crystallographic and solution studies

Abstract Chloride intracellular channels (CLICs) are a family of unique proteins, that were suggested to adopt both soluble and membrane-associated forms. Moreover, following this unusual metamorphic change, CLICs were shown to incorporate into membranes and mediate ion conduction in vitro, suggesti...

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Autores principales:	Alisa Ferofontov, Roi Strulovich, Milit Marom, Moshe Giladi, Yoni Haitin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d8813ac4fc1b461b81311090de4a4bce
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spelling	oai:doaj.org-article:d8813ac4fc1b461b81311090de4a4bce2021-12-02T12:32:59ZInherent flexibility of CLIC6 revealed by crystallographic and solution studies10.1038/s41598-018-25231-z2045-2322https://doaj.org/article/d8813ac4fc1b461b81311090de4a4bce2018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25231-zhttps://doaj.org/toc/2045-2322Abstract Chloride intracellular channels (CLICs) are a family of unique proteins, that were suggested to adopt both soluble and membrane-associated forms. Moreover, following this unusual metamorphic change, CLICs were shown to incorporate into membranes and mediate ion conduction in vitro, suggesting multimerization upon membrane insertion. Here, we present a 1.8 Å resolution crystal structure of the CLIC domain of mouse CLIC6 (mCLIC6). The structure reveals a monomeric arrangement and shows a high degree of structural conservation with other CLICs. Small-angle X-ray scattering (SAXS) analysis of mCLIC6 demonstrated that the overall solution structure is similar to the crystallographic conformation. Strikingly, further analysis of the SAXS data using ensemble optimization method unveiled additional elongated conformations, elucidating high structural plasticity as an inherent property of the protein. Moreover, structure-guided perturbation of the inter-domain interface by mutagenesis resulted in a population shift towards elongated conformations of mCLIC6. Additionally, we demonstrate that oxidative conditions induce an increase in mCLIC6 hydrophobicity along with mild oligomerization, which was enhanced by the presence of membrane mimetics. Together, these results provide mechanistic insights into the metamorphic nature of mCLIC6.Alisa FerofontovRoi StrulovichMilit MaromMoshe GiladiYoni HaitinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-14 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Alisa Ferofontov Roi Strulovich Milit Marom Moshe Giladi Yoni Haitin Inherent flexibility of CLIC6 revealed by crystallographic and solution studies
description	Abstract Chloride intracellular channels (CLICs) are a family of unique proteins, that were suggested to adopt both soluble and membrane-associated forms. Moreover, following this unusual metamorphic change, CLICs were shown to incorporate into membranes and mediate ion conduction in vitro, suggesting multimerization upon membrane insertion. Here, we present a 1.8 Å resolution crystal structure of the CLIC domain of mouse CLIC6 (mCLIC6). The structure reveals a monomeric arrangement and shows a high degree of structural conservation with other CLICs. Small-angle X-ray scattering (SAXS) analysis of mCLIC6 demonstrated that the overall solution structure is similar to the crystallographic conformation. Strikingly, further analysis of the SAXS data using ensemble optimization method unveiled additional elongated conformations, elucidating high structural plasticity as an inherent property of the protein. Moreover, structure-guided perturbation of the inter-domain interface by mutagenesis resulted in a population shift towards elongated conformations of mCLIC6. Additionally, we demonstrate that oxidative conditions induce an increase in mCLIC6 hydrophobicity along with mild oligomerization, which was enhanced by the presence of membrane mimetics. Together, these results provide mechanistic insights into the metamorphic nature of mCLIC6.
format	article
author	Alisa Ferofontov Roi Strulovich Milit Marom Moshe Giladi Yoni Haitin
author_facet	Alisa Ferofontov Roi Strulovich Milit Marom Moshe Giladi Yoni Haitin
author_sort	Alisa Ferofontov
title	Inherent flexibility of CLIC6 revealed by crystallographic and solution studies
title_short	Inherent flexibility of CLIC6 revealed by crystallographic and solution studies
title_full	Inherent flexibility of CLIC6 revealed by crystallographic and solution studies
title_fullStr	Inherent flexibility of CLIC6 revealed by crystallographic and solution studies
title_full_unstemmed	Inherent flexibility of CLIC6 revealed by crystallographic and solution studies
title_sort	inherent flexibility of clic6 revealed by crystallographic and solution studies
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/d8813ac4fc1b461b81311090de4a4bce
work_keys_str_mv	AT alisaferofontov inherentflexibilityofclic6revealedbycrystallographicandsolutionstudies AT roistrulovich inherentflexibilityofclic6revealedbycrystallographicandsolutionstudies AT militmarom inherentflexibilityofclic6revealedbycrystallographicandsolutionstudies AT moshegiladi inherentflexibilityofclic6revealedbycrystallographicandsolutionstudies AT yonihaitin inherentflexibilityofclic6revealedbycrystallographicandsolutionstudies
_version_	1718393949121413120

Inherent flexibility of CLIC6 revealed by crystallographic and solution studies

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