Zn(II) binding causes interdomain changes in the structure and flexibility of the human prion protein

Abstract The cellular prion protein (PrPC) is a mainly α-helical 208-residue protein located in the pre- and postsynaptic membranes. For unknown reasons, PrPC can undergo a structural transition into a toxic, β-sheet rich scrapie isoform (PrPSc) that is responsible for transmissible spongiform encep...

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Autores principales:	Maciej Gielnik, Michał Taube, Lilia Zhukova, Igor Zhukov, Sebastian K. T. S. Wärmländer, Željko Svedružić, Wojciech M. Kwiatek, Astrid Gräslund, Maciej Kozak
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2fe3416e0e5f40d4a4f38ea7f65014b5
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spelling	oai:doaj.org-article:2fe3416e0e5f40d4a4f38ea7f65014b52021-11-08T10:52:53ZZn(II) binding causes interdomain changes in the structure and flexibility of the human prion protein10.1038/s41598-021-00495-02045-2322https://doaj.org/article/2fe3416e0e5f40d4a4f38ea7f65014b52021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-00495-0https://doaj.org/toc/2045-2322Abstract The cellular prion protein (PrPC) is a mainly α-helical 208-residue protein located in the pre- and postsynaptic membranes. For unknown reasons, PrPC can undergo a structural transition into a toxic, β-sheet rich scrapie isoform (PrPSc) that is responsible for transmissible spongiform encephalopathies (TSEs). Metal ions seem to play an important role in the structural conversion. PrPC binds Zn(II) ions and may be involved in metal ion transport and zinc homeostasis. Here, we use multiple biophysical techniques including optical and NMR spectroscopy, molecular dynamics simulations, and small angle X-ray scattering to characterize interactions between human PrPC and Zn(II) ions. Binding of a single Zn(II) ion to the PrPC N-terminal domain via four His residues from the octarepeat region induces a structural transition in the C-terminal α-helices 2 and 3, promotes interaction between the N-terminal and C-terminal domains, reduces the folded protein size, and modifies the internal structural dynamics. As our results suggest that PrPC can bind Zn(II) under physiological conditions, these effects could be important for the physiological function of PrPC.Maciej GielnikMichał TaubeLilia ZhukovaIgor ZhukovSebastian K. T. S. WärmländerŽeljko SvedružićWojciech M. KwiatekAstrid GräslundMaciej KozakNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Maciej Gielnik Michał Taube Lilia Zhukova Igor Zhukov Sebastian K. T. S. Wärmländer Željko Svedružić Wojciech M. Kwiatek Astrid Gräslund Maciej Kozak Zn(II) binding causes interdomain changes in the structure and flexibility of the human prion protein
description	Abstract The cellular prion protein (PrPC) is a mainly α-helical 208-residue protein located in the pre- and postsynaptic membranes. For unknown reasons, PrPC can undergo a structural transition into a toxic, β-sheet rich scrapie isoform (PrPSc) that is responsible for transmissible spongiform encephalopathies (TSEs). Metal ions seem to play an important role in the structural conversion. PrPC binds Zn(II) ions and may be involved in metal ion transport and zinc homeostasis. Here, we use multiple biophysical techniques including optical and NMR spectroscopy, molecular dynamics simulations, and small angle X-ray scattering to characterize interactions between human PrPC and Zn(II) ions. Binding of a single Zn(II) ion to the PrPC N-terminal domain via four His residues from the octarepeat region induces a structural transition in the C-terminal α-helices 2 and 3, promotes interaction between the N-terminal and C-terminal domains, reduces the folded protein size, and modifies the internal structural dynamics. As our results suggest that PrPC can bind Zn(II) under physiological conditions, these effects could be important for the physiological function of PrPC.
format	article
author	Maciej Gielnik Michał Taube Lilia Zhukova Igor Zhukov Sebastian K. T. S. Wärmländer Željko Svedružić Wojciech M. Kwiatek Astrid Gräslund Maciej Kozak
author_facet	Maciej Gielnik Michał Taube Lilia Zhukova Igor Zhukov Sebastian K. T. S. Wärmländer Željko Svedružić Wojciech M. Kwiatek Astrid Gräslund Maciej Kozak
author_sort	Maciej Gielnik
title	Zn(II) binding causes interdomain changes in the structure and flexibility of the human prion protein
title_short	Zn(II) binding causes interdomain changes in the structure and flexibility of the human prion protein
title_full	Zn(II) binding causes interdomain changes in the structure and flexibility of the human prion protein
title_fullStr	Zn(II) binding causes interdomain changes in the structure and flexibility of the human prion protein
title_full_unstemmed	Zn(II) binding causes interdomain changes in the structure and flexibility of the human prion protein
title_sort	zn(ii) binding causes interdomain changes in the structure and flexibility of the human prion protein
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2fe3416e0e5f40d4a4f38ea7f65014b5
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Zn(II) binding causes interdomain changes in the structure and flexibility of the human prion protein

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