title: Tetrameric c-di-GMP mediates effective transcription factor dimerization to control Streptomyces development.
abstract: The cyclic dinucleotide c-di-GMP is a signaling molecule with diverse functions in cellular physiology. Here, we report that c-di-GMP can assemble into a tetramer that mediates the effective dimerization of a transcription factor, BldD, which controls the progression of multicellular differentiation in sporulating actinomycete bacteria. BldD represses expression of sporulation genes during vegetative growth in a manner that depends on c-di-GMP-mediated dimerization. Structural and biochemical analyses show that tetrameric c-di-GMP links two subunits of BldD through their C-terminal domains, which are otherwise separated by ~10 Å and thus cannot effect dimerization directly. Binding of the c-di-GMP tetramer by BldD is selective and requires a bipartite RXD-X8-RXXD signature. The findings indicate a unique mechanism of protein dimerization and the ability of nucleotide signaling molecules to assume alternative oligomeric states to effect different functions.
authors.affiliation: Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
authors.forename: Natalia
authors.initials: N
authors.lastname: Tschowri
authors.affiliation: Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Schumacher
authors.affiliation: Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Schlimpert
authors.affiliation: Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Naga Babu
authors.initials: NB
authors.lastname: Chinnam
authors.affiliation: Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
authors.forename: Kim C
authors.initials: KC
authors.lastname: Findlay
authors.affiliation: Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Brennan
authors.affiliation: Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK. Electronic address: mark.buttner@jic.ac.uk.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Buttner
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism; D019281:Dimerization; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D013171:Spores, Bacterial / Q000378:metabolism; D013302:Streptomyces / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D014157:Transcription Factors; C062025:bis(3',5')-cyclic diguanylic acid; D006152:Cyclic GMP