Proteolytic Regulation in the Biosynthesis of Natural Product Via a ClpP Protease System.

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  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 101282906 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1554-8937 (Electronic) Linking ISSN: 15548929 NLM ISO Abbreviation: ACS Chem Biol Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, D.C. : American Chemical Society, c2006-
    • Subject Terms:
      Endopeptidase Clp*/metabolism ; Proteolysis* ; Biological Products*/metabolism ; Biological Products*/chemistry ; Bacillus subtilis*/enzymology ; Bacillus subtilis*/metabolism ; Bacterial Proteins*/metabolism; Peptide Synthases/metabolism ; Adenosine Triphosphatases/metabolism
    • Abstract:
      Protein degradation is a tightly regulated biological process that maintains bacterial proteostasis. ClpPs are a highly conserved family of serine proteases that associate with the AAA + ATPase (an ATPase associated with diverse cellular activities) to degrade protein substrates. Identification and biochemical characterization of protein substrates for the AAA + ATPase-dependent ClpP degradation systems are considered essential for gaining an understanding of the molecular operation of the complex ClpP degradation machinery. Consequently, expanding the repertoire of protein substrates that can be degraded in vitro and within bacterial cells is necessary. Here, we report that AAA + ATPase-ClpP proteolytic complexes promote degradation of the secondary metabolite surfactin synthetases SrfAA, SrfAB, and SrfAC in Bacillus subtilis . On the basis of in vitro and in-cell studies coupled with activity-based protein profiling of nonribosomal peptide synthetases, we showed that SrfAC is targeted to the ClpC-ClpP proteolytic complex, whereas SrfAA is hydrolyzed not only by the ClpC-ClpP proteolytic complex but also by different ClpP proteolytic complexes. Furthermore, SrfAB does not appear to be a substrate for the ClpC-ClpP proteolytic complex, thereby implying that other ClpP proteolytic complexes are involved in the degradation of this surfactin synthetase. Natural product biosynthesis is regulated by the AAA + ATPase-ClpP degradation system, indicating that protein degradation plays a role in the regulatory stages of biosynthesis. However, few studies have examined the regulation of protein degradation levels. Furthermore, SrfAA, SrfAB, and SrfAC were identified as protein substrates for AAA + ATPase-ClpP degradation systems, thereby contributing to a better understanding of the complex ClpP degradation machinery.
    • Accession Number:
      EC 3.4.21.92 (Endopeptidase Clp)
      0 (Biological Products)
      0 (Bacterial Proteins)
      EC 6.3.2.- (Peptide Synthases)
      EC 3.6.1.- (Adenosine Triphosphatases)
    • Publication Date:
      Date Created: 20240803 Date Completed: 20240816 Latest Revision: 20240816
    • Publication Date:
      20240816
    • Accession Number:
      10.1021/acschembio.4c00304
    • Accession Number:
      39096241