Tetrameric c-di-GMP mediates effective transcription factor dimerization to control Streptomyces development

Cell. 2014 Aug 28;158(5):1136-1147. doi: 10.1016/j.cell.2014.07.022.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism*
  • Crystallography, X-Ray
  • Cyclic GMP / analogs & derivatives*
  • Cyclic GMP / metabolism
  • Dimerization
  • Models, Molecular
  • Molecular Sequence Data
  • Sequence Alignment
  • Spores, Bacterial / metabolism
  • Streptomyces / cytology
  • Streptomyces / growth & development*
  • Streptomyces / metabolism*
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism*


  • Bacterial Proteins
  • Transcription Factors
  • bis(3',5')-cyclic diguanylic acid
  • Cyclic GMP

Associated data

  • PDB/4OAX
  • PDB/4OAY
  • PDB/4OAZ
  • PDB/4OB4