title: The second messenger c-di-AMP inhibits the osmolyte uptake system OpuC in Staphylococcus aureus.
abstract: Staphylococcus aureus is an important opportunistic human pathogen that is highly resistant to osmotic stresses. To survive an increase in osmolarity, bacteria immediately take up potassium ions and small organic compounds known as compatible solutes. The second messenger cyclic diadenosine monophosphate (c-di-AMP) reduces the ability of bacteria to withstand osmotic stress by binding to and inhibiting several proteins that promote potassium uptake. We identified OpuCA, the adenosine triphosphatase (ATPase) component of an uptake system for the compatible solute carnitine, as a c-di-AMP target protein in S aureus and found that the LAC*ΔgdpP strain of S aureus, which overproduces c-di-AMP, showed reduced carnitine uptake. The paired cystathionine-β-synthase (CBS) domains of OpuCA bound to c-di-AMP, and a crystal structure revealed a putative binding pocket for c-di-AMP in the cleft between the two CBS domains. Thus, c-di-AMP inhibits osmoprotection through multiple mechanisms.
authors.affiliation: Section of Microbiology and MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, UK.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Schuster
authors.affiliation: Section of Microbiology and MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, UK.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Bellows
authors.affiliation: Section of Microbiology and MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, UK.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Tosi
authors.affiliation: Section of Microbiology and MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, UK.
authors.forename: Ivan
authors.initials: I
authors.lastname: Campeotto
authors.affiliation: Section of Microbiology and MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, UK.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Corrigan
authors.affiliation: Section of Structural Biology, Department of Medicine, Imperial College London, London SW7 2AZ, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Freemont
authors.affiliation: Section of Microbiology and MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London SW7 2AZ, UK.
authors.forename: Angelika
authors.initials: A
authors.lastname: Gründling
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D002331:Carnitine / Q000378:metabolism; D018360:Crystallography, X-Ray; D015226:Dinucleoside Phosphates / Q000737:chemistry / Q000378:metabolism; D009997:Osmotic Pressure; D000072417:Protein Domains; D015290:Second Messenger Systems; D013211:Staphylococcus aureus / Q000737:chemistry / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins; D015226:Dinucleoside Phosphates; C119750:OpuC protein, bacteria; C528998:cyclic diadenosine phosphate; D002331:Carnitine