한빛사 논문
Leehyeon Kim1,†, Byung-Gil Lee1,5,†, Minki Kim1, Min Kyung Kim1,5, Do Hoon Kwon1,6, Hyunmin Kim2, Heike Brötz-Oesterhelt3,4, Soung-Hun Roh*,2 and Hyun Kyu Song*,1
1Department of Life Sciences, Korea University, Seoul, South Korea
2School of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul, South Korea
3Department of Microbial Bioactive Compounds, Interfaculty Institute of Microbiology and Infection Medicine, University of Tuebingen, Tuebingen, Germany
4Cluster of Excellence Controlling Microbes to Fight Infection, University of Tuebingen, Tuebingen, Germany
5Present address: MRC Laboratory of Molecular Biology, Cambridge, UK
6Present address: Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA
† These authors contributed equally to this work.
*Corresponding author.
Abstract
The ClpP serine peptidase is a tetradecameric degradation molecular machine involved in many physiological processes. It becomes a competent ATP-dependent protease when coupled with Clp-ATPases. Small chemical compounds, acyldepsipeptides (ADEPs), are known to cause the dysregulation and activation of ClpP without ATPases and have potential as novel antibiotics. Previously, structural studies of ClpP from various species revealed its structural details, conformational changes, and activation mechanism. Although product release through side exit pores has been proposed, the detailed driving force for product release remains elusive. Herein, we report crystal structures of ClpP from Bacillus subtilis (BsClpP) in unforeseen ADEP-bound states. Cryo-electron microscopy structures of BsClpP revealed various conformational states under different pH conditions. To understand the conformational change required for product release, we investigated the relationship between substrate hydrolysis and the pH-lowering process. The production of hydrolyzed peptides from acidic and basic substrates by proteinase K and BsClpP lowered the pH values. Our data, together with those of previous findings, provide insight into the molecular mechanism of product release by the ClpP self-compartmentalizing protease.
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