Phosphorylation-induced changes in the PDZ domain of Dishevelled 3

Abstract The PDZ domain of Dishevelled 3 protein belongs to a highly abundant protein recognition motif which typically binds short C-terminal peptides. The affinity of the PDZ towards the peptides could be fine-tuned by a variety of post-translation modifications including phosphorylation. However,...

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Autores principales:	Miroslav Jurásek, Jitender Kumar, Petra Paclíková, Alka Kumari, Konstantinos Tripsianes, Vítězslav Bryja, Robert Vácha
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/69a71e109e3e4b98bed52b98a56b9089
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spelling	oai:doaj.org-article:69a71e109e3e4b98bed52b98a56b90892021-12-02T14:12:43ZPhosphorylation-induced changes in the PDZ domain of Dishevelled 310.1038/s41598-020-79398-52045-2322https://doaj.org/article/69a71e109e3e4b98bed52b98a56b90892021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79398-5https://doaj.org/toc/2045-2322Abstract The PDZ domain of Dishevelled 3 protein belongs to a highly abundant protein recognition motif which typically binds short C-terminal peptides. The affinity of the PDZ towards the peptides could be fine-tuned by a variety of post-translation modifications including phosphorylation. However, how phosphorylations affect the PDZ structure and its interactions with ligands remains elusive. Combining molecular dynamics simulations, NMR titration, and biological experiments, we explored the role of previously reported phosphorylation sites and their mimetics in the Dishevelled PDZ domain. Our observations suggest three major roles for phosphorylations: (1) acting as an on/off PDZ binding switch, (2) allosterically affecting the binding groove, and (3) influencing the secondary binding site. Our simulations indicated that mimetics had similar but weaker effects, and the effects of distinct sites were non-additive. This study provides insight into the Dishevelled regulation by PDZ phosphorylation. Furthermore, the observed effects could be used to elucidate the regulation mechanisms in other PDZ domains.Miroslav JurásekJitender KumarPetra PaclíkováAlka KumariKonstantinos TripsianesVítězslav BryjaRobert VáchaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Miroslav Jurásek Jitender Kumar Petra Paclíková Alka Kumari Konstantinos Tripsianes Vítězslav Bryja Robert Vácha Phosphorylation-induced changes in the PDZ domain of Dishevelled 3
description	Abstract The PDZ domain of Dishevelled 3 protein belongs to a highly abundant protein recognition motif which typically binds short C-terminal peptides. The affinity of the PDZ towards the peptides could be fine-tuned by a variety of post-translation modifications including phosphorylation. However, how phosphorylations affect the PDZ structure and its interactions with ligands remains elusive. Combining molecular dynamics simulations, NMR titration, and biological experiments, we explored the role of previously reported phosphorylation sites and their mimetics in the Dishevelled PDZ domain. Our observations suggest three major roles for phosphorylations: (1) acting as an on/off PDZ binding switch, (2) allosterically affecting the binding groove, and (3) influencing the secondary binding site. Our simulations indicated that mimetics had similar but weaker effects, and the effects of distinct sites were non-additive. This study provides insight into the Dishevelled regulation by PDZ phosphorylation. Furthermore, the observed effects could be used to elucidate the regulation mechanisms in other PDZ domains.
format	article
author	Miroslav Jurásek Jitender Kumar Petra Paclíková Alka Kumari Konstantinos Tripsianes Vítězslav Bryja Robert Vácha
author_facet	Miroslav Jurásek Jitender Kumar Petra Paclíková Alka Kumari Konstantinos Tripsianes Vítězslav Bryja Robert Vácha
author_sort	Miroslav Jurásek
title	Phosphorylation-induced changes in the PDZ domain of Dishevelled 3
title_short	Phosphorylation-induced changes in the PDZ domain of Dishevelled 3
title_full	Phosphorylation-induced changes in the PDZ domain of Dishevelled 3
title_fullStr	Phosphorylation-induced changes in the PDZ domain of Dishevelled 3
title_full_unstemmed	Phosphorylation-induced changes in the PDZ domain of Dishevelled 3
title_sort	phosphorylation-induced changes in the pdz domain of dishevelled 3
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/69a71e109e3e4b98bed52b98a56b9089
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Phosphorylation-induced changes in the PDZ domain of Dishevelled 3

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