Key Points
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Proteins with FIC domains are widespread in pathogenic and non-pathogenic bacteria, where they are found with more than 60 different architectures, suggesting that some subfamilies have conserved regulatory functions.
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Fic proteins use a wide variety of cofactors and protein substrates, but they exploit a very similar catalytic mechanism to carry out post-translational modifications through the addition of AMP, other NMPs, phosphocholine or phosphate to substrate proteins.
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Fic proteins modify diverse target proteins, including small GTPases in animal cells, protein kinases in plants and elongation factor Tu in bacteria. These modifications impair cytoskeletal, trafficking, signalling or translational functions of the target cell.
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The regulation of Fic proteins has only just begun to be investigated. Several Fic families are regulated through the obstruction of their active site by autoinhibition or by antitoxins, or through a phosphodiesterase that removes the post-translational modification. The extent to which each subfamily is regulated and the nature of the regulatory signals remain unknown.
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A major area for future research is the elucidation of the physiological functions of Fic proteins produced by bacterial pathogens, as this could yield opportunities for developing novel antimicrobial compounds.
Abstract
Fic proteins are a family of proteins characterized by the presence of a conserved FIC domain that is involved in the modification of protein substrates by the addition of phosphate-containing compounds, including AMP and other nucleoside monophosphates, phosphocholine and phosphate. Fic proteins are widespread in bacteria, and various pathogenic species secrete Fic proteins as toxins that mediate post-translational modifications of host cell proteins, to interfere with cytoskeletal, trafficking, signalling or translation pathways in the host cell. In this Review, we discuss the current knowledge of the structure, function and regulation of Fic proteins and consider important areas for future research.
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Acknowledgements
The authors thank the members of their laboratories and all of their colleagues from other laboratories whose research is described in this Review. This work was funded by the French Centre National de la Recherche Scientifique, the Agence Nationale de la Recherche and the Fondation pour la Recherche Médicale (J.C.).
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Glossary
- Filamentation
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A bacterial growth mode in which cells grow without division, resulting in a filamentous morphology. This type of growth occurs in response to various stresses.
- Secretion systems
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Protein nanomachines that deliver DNA and bacterially encoded effector proteins into target cells.
- Small GTPases
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A superfamily of GTP-binding proteins that are regulated by GDP and GTP, and by changing localization to the membrane or the cytosol. In turn, these GTPases regulate a variety of processes in eukaryotic cells, including cell growth and differentiation, dynamics of the actin cytoskeleton and membrane traffic. RAB and RHO small GTPases carry a prenyl lipid in their carboxyl terminus, and this moiety is necessary for their reversible attachment to membranes.
- Cofactors
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Chemical compounds that participate in the reaction catalysed by an enzyme.
- Switch regions
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Pertaining to small GTPases: two flexible regions that are found in all small GTPases; these regions change conformation on binding to GTP and are directly involved in the interactions of GTPases with regulators and effectors.
- Inflammasome
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A multiprotein oligomer that activates an inflammatory cascade during an infection.
- Guanine nucleotide exchange factors
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(GEFs). Activators of small GTPases. GEFs function by stimulating GDP–GTP exchange, and they often have membrane-binding domains that increase their activities by colocalizing them with their cognate small GTPases.
- Guanine nucleotide dissociation inhibitors
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(GDIs). Negative regulators of RHO- and RAB-family small GTPases. GDIs inactivate their targets by displacing them from membranes, forming a cytosolic complex with the small GTPases by masking their prenyl group.
- Elongation factor Tu
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(EF-Tu). A prokaryotic elongation factor that binds tRNA molecules and shuttles them to a free site on the ribosome. EF-Tu is a GTP-binding protein related to small GTPases, and it undergoes large conformational changes on activation by GDP–GTP exchange and on inactivation by GTP hydrolysis.
- Persisters
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Non-replicating cells that are present in low numbers in bacterial populations and show increased survival under a variety of environmental stresses, including antibiotic treatment.
- Glia cells
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Non-neuronal brain cells that regulate brain homeostasis.
- Unfolded-protein response
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A cellular stress response that is activated by the accumulation of misfolded proteins in the endoplasmic reticulum.
- Nucleophilic attack
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The donation of electrons by one electron-rich atom (the nucleophile) to another, electron-poor atom (the electrophile) to form a new chemical bond during enzymatic catalysis.
- β-sheet augmentation
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A mode of protein–protein interaction in which a β-strand from the ligand pairs with the edge of a preformed β-sheet of the acceptor protein.
- Structural-genomics consortium
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A large-scale initiative to determine protein structures and make them immediately available to the scientific community, often before anything is known about the function of the protein. About half the structures of Fic proteins have been determined by such structural-genomics centres.
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Roy, C., Cherfils, J. Structure and function of Fic proteins. Nat Rev Microbiol 13, 631–640 (2015). https://doi.org/10.1038/nrmicro3520
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DOI: https://doi.org/10.1038/nrmicro3520
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