Regulation of the Human Phosphatase PTPN4 by the inter-domain linker connecting the PDZ and the phosphatase domains

Abstract Human protein tyrosine phosphatase non-receptor type 4 (PTPN4) has been shown to prevent cell death. The active form of human PTPN4 consists of two globular domains, a PDZ (PSD-95/Dlg/ZO-1) domain and a phosphatase domain, tethered by a flexible linker. Targeting its PDZ domain abrogates th...

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Autores principales:	Célia Caillet-Saguy, Angelo Toto, Raphael Guerois, Pierre Maisonneuve, Eva di Silvio, Kristi Sawyer, Stefano Gianni, Nicolas Wolff
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cee468f5e6294dbb87c0a2a532e72493
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spelling	oai:doaj.org-article:cee468f5e6294dbb87c0a2a532e724932021-12-02T16:06:12ZRegulation of the Human Phosphatase PTPN4 by the inter-domain linker connecting the PDZ and the phosphatase domains10.1038/s41598-017-08193-62045-2322https://doaj.org/article/cee468f5e6294dbb87c0a2a532e724932017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08193-6https://doaj.org/toc/2045-2322Abstract Human protein tyrosine phosphatase non-receptor type 4 (PTPN4) has been shown to prevent cell death. The active form of human PTPN4 consists of two globular domains, a PDZ (PSD-95/Dlg/ZO-1) domain and a phosphatase domain, tethered by a flexible linker. Targeting its PDZ domain abrogates this protection and triggers apoptosis. We previously demonstrated that the PDZ domain inhibits the phosphatase activity of PTPN4 and that the mere binding of a PDZ ligand is sufficient to release the catalytic inhibition. We demonstrate here that the linker connecting the PDZ domain and the phosphatase domain is involved in the regulation of the phosphatase activity in both PDZ-related inhibition and PDZ ligand-related activation events. We combined bioinformatics and kinetic studies to decipher the role of the linker in the PTPN4 activity. By comparing orthologous sequences, we identified a conserved patch of hydrophobic residues in the linker. We showed that mutations in this patch affect the regulation of the PTPN4 bidomain indicating that the PDZ-PDZ ligand regulation of PTPN4 is a linker-mediated mechanism. However, the mutations do not alter the binding of the PDZ ligand. This study strengthens the notion that inter-domain linker can be of functional importance in enzyme regulation of large multi-domain proteins.Célia Caillet-SaguyAngelo TotoRaphael GueroisPierre MaisonneuveEva di SilvioKristi SawyerStefano GianniNicolas WolffNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Célia Caillet-Saguy Angelo Toto Raphael Guerois Pierre Maisonneuve Eva di Silvio Kristi Sawyer Stefano Gianni Nicolas Wolff Regulation of the Human Phosphatase PTPN4 by the inter-domain linker connecting the PDZ and the phosphatase domains
description	Abstract Human protein tyrosine phosphatase non-receptor type 4 (PTPN4) has been shown to prevent cell death. The active form of human PTPN4 consists of two globular domains, a PDZ (PSD-95/Dlg/ZO-1) domain and a phosphatase domain, tethered by a flexible linker. Targeting its PDZ domain abrogates this protection and triggers apoptosis. We previously demonstrated that the PDZ domain inhibits the phosphatase activity of PTPN4 and that the mere binding of a PDZ ligand is sufficient to release the catalytic inhibition. We demonstrate here that the linker connecting the PDZ domain and the phosphatase domain is involved in the regulation of the phosphatase activity in both PDZ-related inhibition and PDZ ligand-related activation events. We combined bioinformatics and kinetic studies to decipher the role of the linker in the PTPN4 activity. By comparing orthologous sequences, we identified a conserved patch of hydrophobic residues in the linker. We showed that mutations in this patch affect the regulation of the PTPN4 bidomain indicating that the PDZ-PDZ ligand regulation of PTPN4 is a linker-mediated mechanism. However, the mutations do not alter the binding of the PDZ ligand. This study strengthens the notion that inter-domain linker can be of functional importance in enzyme regulation of large multi-domain proteins.
format	article
author	Célia Caillet-Saguy Angelo Toto Raphael Guerois Pierre Maisonneuve Eva di Silvio Kristi Sawyer Stefano Gianni Nicolas Wolff
author_facet	Célia Caillet-Saguy Angelo Toto Raphael Guerois Pierre Maisonneuve Eva di Silvio Kristi Sawyer Stefano Gianni Nicolas Wolff
author_sort	Célia Caillet-Saguy
title	Regulation of the Human Phosphatase PTPN4 by the inter-domain linker connecting the PDZ and the phosphatase domains
title_short	Regulation of the Human Phosphatase PTPN4 by the inter-domain linker connecting the PDZ and the phosphatase domains
title_full	Regulation of the Human Phosphatase PTPN4 by the inter-domain linker connecting the PDZ and the phosphatase domains
title_fullStr	Regulation of the Human Phosphatase PTPN4 by the inter-domain linker connecting the PDZ and the phosphatase domains
title_full_unstemmed	Regulation of the Human Phosphatase PTPN4 by the inter-domain linker connecting the PDZ and the phosphatase domains
title_sort	regulation of the human phosphatase ptpn4 by the inter-domain linker connecting the pdz and the phosphatase domains
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/cee468f5e6294dbb87c0a2a532e72493
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_version_	1718385115426455552

Regulation of the Human Phosphatase PTPN4 by the inter-domain linker connecting the PDZ and the phosphatase domains

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