Crystal structure of a low molecular weight activator Blm-pep with yeast 20S proteasome – insights into the enzyme activation mechanism

Abstract Proteasomes are responsible for protein turnover in eukaryotic cells, degrading short-lived species but also removing improperly folded or oxidatively damaged ones. Dysfunction of a proteasome results in gradual accumulation of misfolded/damaged proteins, leading to their aggregation. It ha...

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Autores principales:	Julia Witkowska, Małgorzata Giżyńska, Przemysław Grudnik, Przemysław Golik, Przemysław Karpowicz, Artur Giełdoń, Grzegorz Dubin, Elżbieta Jankowska
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d403208b73eb48f4be63d1e3819f8b3b
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spelling	oai:doaj.org-article:d403208b73eb48f4be63d1e3819f8b3b2021-12-02T16:08:12ZCrystal structure of a low molecular weight activator Blm-pep with yeast 20S proteasome – insights into the enzyme activation mechanism10.1038/s41598-017-05997-42045-2322https://doaj.org/article/d403208b73eb48f4be63d1e3819f8b3b2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05997-4https://doaj.org/toc/2045-2322Abstract Proteasomes are responsible for protein turnover in eukaryotic cells, degrading short-lived species but also removing improperly folded or oxidatively damaged ones. Dysfunction of a proteasome results in gradual accumulation of misfolded/damaged proteins, leading to their aggregation. It has been postulated that proteasome activators may facilitate removal of such aggregation-prone proteins and thus prevent development of neurodegenerative disorders. However, the discovery of pharmacologically relevant compounds is hindered by insufficient structural understanding of the activation process. In this study we provide a model peptidic activator of human proteasome and analyze the structure-activity relationship within this novel scaffold. The binding mode of the activator at the relevant pocket within the proteasome has been determined by X-ray crystallography. This crystal structure provides an important basis for rational design of pharmacological compounds. Moreover, by providing a novel insight into the proteasome gating mechanism, our results allow the commonly accepted model of proteasome regulation to be revisited.Julia WitkowskaMałgorzata GiżyńskaPrzemysław GrudnikPrzemysław GolikPrzemysław KarpowiczArtur GiełdońGrzegorz DubinElżbieta JankowskaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Julia Witkowska Małgorzata Giżyńska Przemysław Grudnik Przemysław Golik Przemysław Karpowicz Artur Giełdoń Grzegorz Dubin Elżbieta Jankowska Crystal structure of a low molecular weight activator Blm-pep with yeast 20S proteasome – insights into the enzyme activation mechanism
description	Abstract Proteasomes are responsible for protein turnover in eukaryotic cells, degrading short-lived species but also removing improperly folded or oxidatively damaged ones. Dysfunction of a proteasome results in gradual accumulation of misfolded/damaged proteins, leading to their aggregation. It has been postulated that proteasome activators may facilitate removal of such aggregation-prone proteins and thus prevent development of neurodegenerative disorders. However, the discovery of pharmacologically relevant compounds is hindered by insufficient structural understanding of the activation process. In this study we provide a model peptidic activator of human proteasome and analyze the structure-activity relationship within this novel scaffold. The binding mode of the activator at the relevant pocket within the proteasome has been determined by X-ray crystallography. This crystal structure provides an important basis for rational design of pharmacological compounds. Moreover, by providing a novel insight into the proteasome gating mechanism, our results allow the commonly accepted model of proteasome regulation to be revisited.
format	article
author	Julia Witkowska Małgorzata Giżyńska Przemysław Grudnik Przemysław Golik Przemysław Karpowicz Artur Giełdoń Grzegorz Dubin Elżbieta Jankowska
author_facet	Julia Witkowska Małgorzata Giżyńska Przemysław Grudnik Przemysław Golik Przemysław Karpowicz Artur Giełdoń Grzegorz Dubin Elżbieta Jankowska
author_sort	Julia Witkowska
title	Crystal structure of a low molecular weight activator Blm-pep with yeast 20S proteasome – insights into the enzyme activation mechanism
title_short	Crystal structure of a low molecular weight activator Blm-pep with yeast 20S proteasome – insights into the enzyme activation mechanism
title_full	Crystal structure of a low molecular weight activator Blm-pep with yeast 20S proteasome – insights into the enzyme activation mechanism
title_fullStr	Crystal structure of a low molecular weight activator Blm-pep with yeast 20S proteasome – insights into the enzyme activation mechanism
title_full_unstemmed	Crystal structure of a low molecular weight activator Blm-pep with yeast 20S proteasome – insights into the enzyme activation mechanism
title_sort	crystal structure of a low molecular weight activator blm-pep with yeast 20s proteasome – insights into the enzyme activation mechanism
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/d403208b73eb48f4be63d1e3819f8b3b
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Crystal structure of a low molecular weight activator Blm-pep with yeast 20S proteasome – insights into the enzyme activation mechanism

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