The novel structure of a cytosolic M14 metallocarboxypeptidase (CCP) from Pseudomonas aeruginosa: A model for mammalian CCPs

Anabel Otero, Mónica Rodríguez De La Vega, Sebastian Tanco, Julia Lorenzo, Francesc X. Avilés, David Reverter

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

Abstract

PaCCP is a metallocarboxypeptidase (MCP) of the M14 family from Pseudomonas aeruginosa, which belongs to a bacterial clade of carboxypeptidases that are homologous to the recently discovered M14D subfamily of human nonsecretory cytosolic carboxypeptidases (CCPs). CCPs are intracellular peptidases involved, among other roles, in the post-translational modifications of tubulin. Here we report the crystal structure of PaCCP at high resolution (1.6 Å). Its 375 residues are folded in a novel β-sandwich N-terminal domain followed by the classical carboxypeptidase α/β-hydrolase domain, this one in a shorter and more compact form. The former is unique in the whole family and does not have sequential or structural homology with other domains that are usually flanking the latter, like the prodomain of the M14A subfamily or the C-terminal transthyretin/prealbumin-like domains of the M14B subfamily. PaCCP does not display activity against small carboxypeptidase substrates, so in this form it might constitute an inactive precursor of the protease. Structural results derived from cocrystallization with well-known inhibitors of MCPs indicate that the enzyme might only possess C-terminal hydrolase activity against cellular substrates of particular specificity and/or when undergoes structural rearrangements. The derived PaCCP structure allows a first structural insight into the more complex and largely unknown mammalian CCP subfamily. © FASEB.
Original languageEnglish
Pages (from-to)3754-3764
JournalFASEB Journal
Volume26
DOIs
Publication statusPublished - 1 Sep 2012

Keywords

  • Crystal structure
  • Inhibitor
  • Metalloprotease
  • Tubulin

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