Molecular basis of pheromone selectivity and interaction by the competence activator ComR in streptococci
(2017) 12th International Symposium on Lactic Acid Bacteria — Location: Egmond aan Zee
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- Authors
Ledesma-García, Laura 
- Abstract
- ComRS is a newly identified cell-to-cell communication system in many streptococci species that activates the competence state for natural transformation, antimicrobial peptide secretion and, in some cases, biofilm formation, three processes that affect microbial population dynamics. The ComRS system includes the pheromone ComS, and the cytoplasmic effector ComR, a member of the RRNPP superfamily which displays an N-terminal DNA-binding domain (HTH) and a C-terminal TPR-domain interacting with the peptide. The weak conservation of TPR-domains, together with the strictness vs. promiscuity of diverse ComR orthologs in presence of non-cognate peptides, suggest a co-evolution between TPR-domains and their corresponding pheromones under species-specific specialization. The ComRS-DNA ternary complex crystal structure of Streptococcus thermophilus combined with a mutational analysis allowed the discrimination of residues involved in ComS binding/activation. From these results, a novel activation mechanism that was unknown for this family of regulators was proposed. In this model, transcriptional activation is prevented in absence of the peptide by sequestration of the HTH domain, while peptide interaction induces release of this sequestered domain and ComR dimerization to allow DNA binding. Moreover, crystallization of ComRS also disclosed precious information about peptide-TPR domain recognition, highlighting regions likely to be involved in specificity. In order to verify their implication, we have tested competence activation by chimeric ComRs (i.e. hybrid proteins between ComR orthologs of S.thermophilus and S.vestibularis). Strict ComR of S. vestibularis was chosen due to the role of this species as opportunistic human pathogen. Currently, several mutants with altered peptide recognition are under investigation. This study will provide the structural basis necessary for the rational design of inhibitors, and will contribute to develop antimicrobial strategies for the control of pathogenic streptococci.
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Ledesma-García, L. (2017). Molecular basis of pheromone selectivity and interaction by the competence activator ComR in streptococci. 12th International Symposium on Lactic Acid Bacteria, Egmond aan Zee. https://hdl.handle.net/2078.5/120831