title: Complex structure and biochemical characterization of the Staphylococcus aureus cyclic diadenylate monophosphate (c-di-AMP)-binding protein PstA, the founding member of a new signal transduction protein family.
abstract: Signaling nucleotides are integral parts of signal transduction systems allowing bacteria to cope with and rapidly respond to changes in the environment. The Staphylococcus aureus PII-like signal transduction protein PstA was recently identified as a cyclic diadenylate monophosphate (c-di-AMP)-binding protein. Here, we present the crystal structures of the apo- and c-di-AMP-bound PstA protein, which is trimeric in solution as well as in the crystals. The structures combined with detailed bioinformatics analysis revealed that the protein belongs to a new family of proteins with a similar core fold but with distinct features to classical PII proteins, which usually function in nitrogen metabolism pathways in bacteria. The complex structure revealed three identical c-di-AMP-binding sites per trimer with each binding site at a monomer-monomer interface. Although distinctly different from other cyclic-di-nucleotide-binding sites, as the half-binding sites are not symmetrical, the complex structure also highlighted common features for c-di-AMP-binding sites. A comparison between the apo and complex structures revealed a series of conformational changes that result in the ordering of two anti-parallel β-strands that protrude from each monomer and allowed us to propose a mechanism on how the PstA protein functions as a signaling transduction protein.
authors.affiliation: From the Section of Microbiology and MRC Centre for Molecular Bacteriology and Infection.
authors.forename: Ivan
authors.initials: I
authors.lastname: Campeotto
authors.affiliation: From the Section of Microbiology and MRC Centre for Molecular Bacteriology and Infection.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Section of Microbiology and MRC Centre for Molecular Bacteriology and Infection.
authors.forename: Miroslav G
authors.initials: MG
authors.lastname: Mladenov
authors.affiliation: Section of Structural Biology, Department of Medicine, Imperial College London, London SW7 2AZ, United Kingdom p.freemont@imperial.ac.uk.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Freemont
authors.affiliation: From the Section of Microbiology and MRC Centre for Molecular Bacteriology and Infection, a.grundling@imperial.ac.uk.
authors.forename: Angelika
authors.initials: A
authors.lastname: Gründling
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000378:metabolism*; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism*; D002352:Carrier Proteins; D019295:Computational Biology; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013211:Staphylococcus aureus / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins; D002352:Carrier Proteins; C078408:phosphate-specific transport protein A, bacteria
keywords: Bacterial Signal Transduction; Bioinformatics; Complex; Crystal Structure; Nucleotide; Staphylococcus aureus (S. aureus)