Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 44, Pages 30668-30679Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.599381
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Funding
- National Institutes of Health (NIH), NIAID [AI65359]
- Lawrence Livermore National Laboratory (LLNL) Laboratory-directed Research and Development (LDRD) [06-ERD-057, 012-ERD-031]
- United States Department of Energy by Lawrence Livermore National Laboratory [DE-AC52-07NA27344]
- United States Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- National Institutes of Health, NIGMS [P41GM103393]
- NIH, NCI [Y1-CO-1020]
- NIH, NIGMS [Y1-GM-1104, P41 GM103403]
- NIH, NCRR [5P41RR015301-10]
- DOE [DE-AC02-06CH11357]
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Francisella tularensis is the etiological agent of tularemia, or rabbit fever. Although F. tularensis is a recognized biothreat agent with broad and expanding geographical range, its mechanism of infection and environmental persistence remain poorly understood. Previously, we identified seven F. tularensis proteins that induce a rapid encystment phenotype (REP) in the free-living amoeba, Acanthamoeba castellanii. Encystment is essential to the pathogen's long term intracellular survival in the amoeba. Here, we characterize the cellular and molecular function of REP34, a REP protein with a mass of 34 kDa. A REP34 knock-out strain of F. tularensis has a reduced ability to both induce encystment in A. castellanii and invade human macrophages. We determined the crystal structure of REP34 to 2.05-angstrom resolution and demonstrate robust carboxypeptidase B-like activity for the enzyme. REP34 is a zinc-containing monomeric protein with close structural homology to the metallocarboxypeptidase family of peptidases. REP34 possesses a novel topology and substrate binding pocket that deviates from the canonical funnelin structure of carboxypeptidases, putatively resulting in a catalytic role for a conserved tyrosine and distinct S1' recognition site. Taken together, these results identify REP34 as an active carboxypeptidase, implicate the enzyme as a potential key F. tularensis effector protein, and may help elucidate a mechanistic understanding of F. tularensis infection of phagocytic cells.
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