The structure of caseinolytic protease subunit ClpP2 reveals a functional model of the caseinolytic protease system from Chlamydia trachomatis

Jahaun Azadmanesh, Mohamed A. Seleem, Lucas Struble, Nicholas A. Wood, Derek J. Fisher, Jeffrey J. Lovelace, Antonio Artigues, Aron W. Fenton, Gloria E.O. Borgstahl, Scot P. Ouellette, Martin Conda-Sheridan

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Chlamydia trachomatis (ct) is the most reported bacterial sexually transmitted infection worldwide and the leading cause of preventable blindness. Caseinolytic proteases (ClpP) from pathogenic bacteria are attractive antibiotic targets, particularly for bacterial species that form persister colonies with phenotypic resistance against common antibiotics. ClpP functions as a multisubunit proteolytic complex, and bacteria are eradicated when ClpP is disrupted. Although crucial for chlamydial development and the design of agents to treat chlamydia, the structures of ctClpP1 and ctClpP2 have yet to be solved. Here, we report the first crystal structure of full-length ClpP2 as an inactive homotetradecamer in a complex with a candidate antibiotic at 2.66 Å resolution. The structure details the functional domains of the ClpP2 protein subunit and includes the handle domain, which is integral to proteolytic activation. In addition, hydrogen-deuterium exchange mass spectroscopy probed the dynamics of ClpP2, and molecular modeling of ClpP1 predicted an assembly with ClpP2. By leveraging previous enzymatic experiments, we constructed a model of ClpP2 activation and its interaction with the protease subunits ClpP1 and ClpX. The structural information presented will be relevant for future rational drug design against these targets and will lead to a better understanding of ClpP complex formation and activation within this important human pathogen.

Original languageEnglish (US)
Article number102762
JournalJournal of Biological Chemistry
Volume299
Issue number1
DOIs
StatePublished - Jan 2023

Keywords

  • Chlamydia
  • ClpP
  • caseinolytic protease
  • crystal structure

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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