Structural Basis for the Differential Regulatory Roles of the PDZ Domain in C-Terminal Processing Proteases

ABSTRACT Carboxyl (C)-terminal processing proteases (CTPs) participate in protective and regulatory proteolysis in bacteria. The PDZ domain is central to the activity of CTPs but plays inherently different regulatory roles. For example, the PDZ domain inhibits the activity of the signaling protease...

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Autores principales:	Chuang-Kai Chueh, Nilanjan Som, Lu-Chu Ke, Meng-Ru Ho, Manjula Reddy, Chung-I Chang
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	PDZ domain enzyme activation mechanisms of action proteases CTP Prc Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/fe754ed0d6df487baa5dc3b3e9d38781
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spelling	oai:doaj.org-article:fe754ed0d6df487baa5dc3b3e9d387812021-11-15T16:22:10ZStructural Basis for the Differential Regulatory Roles of the PDZ Domain in C-Terminal Processing Proteases10.1128/mBio.01129-192150-7511https://doaj.org/article/fe754ed0d6df487baa5dc3b3e9d387812019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01129-19https://doaj.org/toc/2150-7511ABSTRACT Carboxyl (C)-terminal processing proteases (CTPs) participate in protective and regulatory proteolysis in bacteria. The PDZ domain is central to the activity of CTPs but plays inherently different regulatory roles. For example, the PDZ domain inhibits the activity of the signaling protease CtpB by blocking the active site but is required for the activation of Prc (or Tsp), a tail-specific protease that degrades SsrA-tagged proteins. Here, by structural and functional analyses, we show that in the unliganded resting state of Prc, the PDZ domain is docked inside the bowl-shaped scaffold without contacting the active site, which is kept in a default misaligned conformation. In Prc, a hydrophobic substrate sensor distinct from CtpB engages substrate binding to the PDZ domain and triggers a structural remodeling to align the active-site residues. Therefore, this work reveals the structural basis for understanding the contrasting roles of the PDZ domain in the regulation of CTPs. IMPORTANCE Prc, also known previously as Tsp, is the founding member of the carboxyl-terminal processing protease (CTP) family of PDZ domain-containing proteases that include CtpA and CtpB. The substrate-binding PDZ domain is responsible for regulating the protease activity of CTP proteases; however, the regulatory role of PDZ domain is stimulatory in Prc but inhibitory in CtpA/B. By determining a series of crystal structures of Prc in the unliganded resting state, this study presents the structural basis for PDZ-dependent activation of Prc, the results of which explain the contrasting roles of the PDZ domain in the regulation of the protease activity of CTPs.Chuang-Kai ChuehNilanjan SomLu-Chu KeMeng-Ru HoManjula ReddyChung-I ChangAmerican Society for MicrobiologyarticlePDZ domainenzyme activationmechanisms of actionproteasesCTPPrcMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	PDZ domain enzyme activation mechanisms of action proteases CTP Prc Microbiology QR1-502
spellingShingle	PDZ domain enzyme activation mechanisms of action proteases CTP Prc Microbiology QR1-502 Chuang-Kai Chueh Nilanjan Som Lu-Chu Ke Meng-Ru Ho Manjula Reddy Chung-I Chang Structural Basis for the Differential Regulatory Roles of the PDZ Domain in C-Terminal Processing Proteases
description	ABSTRACT Carboxyl (C)-terminal processing proteases (CTPs) participate in protective and regulatory proteolysis in bacteria. The PDZ domain is central to the activity of CTPs but plays inherently different regulatory roles. For example, the PDZ domain inhibits the activity of the signaling protease CtpB by blocking the active site but is required for the activation of Prc (or Tsp), a tail-specific protease that degrades SsrA-tagged proteins. Here, by structural and functional analyses, we show that in the unliganded resting state of Prc, the PDZ domain is docked inside the bowl-shaped scaffold without contacting the active site, which is kept in a default misaligned conformation. In Prc, a hydrophobic substrate sensor distinct from CtpB engages substrate binding to the PDZ domain and triggers a structural remodeling to align the active-site residues. Therefore, this work reveals the structural basis for understanding the contrasting roles of the PDZ domain in the regulation of CTPs. IMPORTANCE Prc, also known previously as Tsp, is the founding member of the carboxyl-terminal processing protease (CTP) family of PDZ domain-containing proteases that include CtpA and CtpB. The substrate-binding PDZ domain is responsible for regulating the protease activity of CTP proteases; however, the regulatory role of PDZ domain is stimulatory in Prc but inhibitory in CtpA/B. By determining a series of crystal structures of Prc in the unliganded resting state, this study presents the structural basis for PDZ-dependent activation of Prc, the results of which explain the contrasting roles of the PDZ domain in the regulation of the protease activity of CTPs.
format	article
author	Chuang-Kai Chueh Nilanjan Som Lu-Chu Ke Meng-Ru Ho Manjula Reddy Chung-I Chang
author_facet	Chuang-Kai Chueh Nilanjan Som Lu-Chu Ke Meng-Ru Ho Manjula Reddy Chung-I Chang
author_sort	Chuang-Kai Chueh
title	Structural Basis for the Differential Regulatory Roles of the PDZ Domain in C-Terminal Processing Proteases
title_short	Structural Basis for the Differential Regulatory Roles of the PDZ Domain in C-Terminal Processing Proteases
title_full	Structural Basis for the Differential Regulatory Roles of the PDZ Domain in C-Terminal Processing Proteases
title_fullStr	Structural Basis for the Differential Regulatory Roles of the PDZ Domain in C-Terminal Processing Proteases
title_full_unstemmed	Structural Basis for the Differential Regulatory Roles of the PDZ Domain in C-Terminal Processing Proteases
title_sort	structural basis for the differential regulatory roles of the pdz domain in c-terminal processing proteases
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/fe754ed0d6df487baa5dc3b3e9d38781
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Structural Basis for the Differential Regulatory Roles of the PDZ Domain in C-Terminal Processing Proteases

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