The HtrA protease from Streptococcus pneumoniae digests both denatured proteins and the competence-stimulating peptide

Marco Cassone, Alyssa L. Gagne, Lynn A. Spruce, Steven H. Seeholzer, Michael E. Sebert

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


The HtrA protease of Streptococcus pneumoniae functions both in a general stress response role and as an error sensor that specifically represses genetic competence when the overall level of biosynthetic errors in cellular proteins is low. However, the mechanism through which HtrA inhibits development of competence has been unknown. We found that HtrA digested the pneumococcal competence-stimulating peptide (CSP) and constituted the primary extracytoplasmic CSP-degrading activity in cultures of S. pneumoniae. Mass spectrometry demonstrated that cleavage predominantly followed residue Phe-8 of the CSP-1 isoform of the peptide within its central hydrophobic patch, and in competition assays, both CSP-1 and CSP-2 interacted with HtrA with similar efficiencies. More generally, analysis of β-casein digestion and of digestion within HtrA itself revealed a preference for substrates with non-polar residues at the P1 site. Consistent with a specificity for exposed hydrophobic residues, competition from native BSA only weakly inhibited digestion of CSP, but denaturation converted BSA into a strong competitive inhibitor of such proteolysis. Together these findings support a model in which digestion of CSP by HtrA is reduced in the presence of other unfolded proteins that serve as alternative targets for degradation. Such competition may provide a mechanism by which HtrA functions in a quality control capacity to monitor the frequency of biosynthetic errors that result in protein misfolding.

Original languageEnglish (US)
Pages (from-to)38449-38459
Number of pages11
JournalJournal of Biological Chemistry
Issue number46
StatePublished - Nov 9 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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