Abstract
Streptomycetes are notable for their complex life cycle and production of most clinically important antibiotics. A key factor that controls entry into development and the onset of antibiotic production is the 68-residue protein, BldC. BldC is a putative DNA-binding protein related to MerR regulators, but lacks coiled-coil dimerization and effector-binding domains characteristic of classical MerR proteins. Hence, the molecular function of the protein has been unclear. Here we show that BldC is indeed a DNA-binding protein and controls a regulon that includes other key developmental regulators. Intriguingly, BldC DNA-binding sites vary significantly in length. Our BldC-DNA structures explain this DNA-binding capability by revealing that BldC utilizes a DNA-binding mode distinct from MerR and other known regulators, involving asymmetric head-to-tail oligomerization on DNA direct repeats that results in dramatic DNA distortion. Notably, BldC-like proteins radiate throughout eubacteria, establishing BldC as the founding member of a new structural family of regulators.
Highlights
Streptomycetes are notable for their complex life cycle and production of most clinically important antibiotics
A congenic bldC null mutant was used as a control to eliminate any potential signals that might arise from cross-reaction of the antibody with other transcription factors. ~280 BldC-specific peaks were detected (P-value
Promoter sites bound by BldC are found upstream of genes encoding many key transcriptional regulators of the Streptomyces developmental cascade including bldM, whiB, whiD, whiH, whiI, sigF, and bldC itself, in addition to others encoding proteins involved in chromosome segregation and condensation during sporulation such as smeA-sffA25 and hupS26 (Fig. 1b and Supplementary Data 1) and genes that influence antibiotic production, the conservon cvnA1 and the serinethreonine protein kinase, afsK28
Summary
Streptomycetes are notable for their complex life cycle and production of most clinically important antibiotics. Using a battery of structural, biochemical, and in vivo approaches, we show here that BldC functions as a pleotropic regulator of Streptomyces development by employing a unique mode of DNA binding for a transcription factor that involves asymmetric head-to-tail oligomerization on DNA direct repeats of varying number with concomitant distortion of the DNA. This mode of DNA binding defines a new family of transcription regulatory proteins that we designate the BldC family
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