Crystal structure and activity studies of the C11 cysteine peptidase from parabacteroides merdae in the human gut microbiome

Karen McLuskey, Jaspreet S. Grewal, Debanu Das, Adam Godzik, Scott A. Lesley, Ashley M. Deacon, Graham H. Coombs, Marc-André Elsliger, Ian A. Wilson, Jeremy C. Mottram

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2 Citations (Scopus)
13 Downloads (Pure)


Clan CD cysteine peptidases, a structurally related group of peptidases that include mammalian caspases, exhibit a wide range of important functions, along with a variety of specificities and activation mechanisms. However, for the clostripain family (denoted C11), little is currently known. Here, we describe the first crystal structure of a C11 protein from the human gut bacterium, Parabacteroides merdae (PmC11), determined to 1.7-Å resolution. PmC11 is a monomeric cysteine peptidase that comprises an extended caspase-likeα/β/α sandwich and an unusual C-terminal domain. It shares core structural elements with clan CD cysteine peptidases but otherwise structurally differs from the other families in the clan. These studies also revealed a well ordered break in the polypeptide chain at Lys147, resulting in a large conformational rearrangement close to the active site. Biochemical and kinetic analysis revealed Lys147 to be an intramolecular processing site at which cleavage is required for full activation of the enzyme, suggesting an autoinhibitory mechanism for self-preservation. PmC11 has an acidic binding pocket and a preference for basic substrates, and accepts substrates with Arg and Lys in P1 and does not require Ca2+ for activity. Collectively, these data provide insights into the mechanism and activity of PmC11 and a detailed framework for studies on C11 peptidases from other phylogenetic kingdoms.

Original languageEnglish
Pages (from-to)9482-9491
Number of pages10
JournalJournal of Biological Chemistry
Issue number18
Early online date3 Mar 2016
Publication statusPublished - 29 Apr 2016


  • C-terminal domain
  • crystal structure
  • cysteine protease
  • enzyme
  • proteolysis
  • active site
  • domain
  • kinteoplast


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