Tetrameric c-di-GMP Mediates Effective Transcription Factor Dimerization to Control Streptomyces Development

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. [Display omitted] •c-di-GMP controls development in the multicellular bacteria Streptomyces•c-di-GMP developmental signaling is directly mediated by the master regulator BldD•A heretofore unseen tetrameric form of c-di-GMP binds BldD to effect its dimerization•BldD-(c-di-GMP) represses transcription of sporulation genes during vegetative growth A ci-d-GMP tetramer functions as molecular glue for dimerization of a transcription factor leading to its activation, which is important for developmental transitions in a sporulating bacterium.