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S. pneumoniae is the leading cause of community-acquired infections worldwide. Its global success might in part be explained by its genetic transformation, which consists of the internalization and the incorporation in the bacterial chromosome of exogenous DNA. Transformation is turned on in cells which are in a physiological state called competence. The induction of the competent state depends on the two-component regulatory system ComD-ComE. The response regulator (RR) ComE is phosphorylated by the histidine-kinase ComD, and acts as transcriptional activator of a large set of competencespecific operons. These genes encode in particular proteins involved in binding, uptake, processing, and recombination of exogenous DNA, but they are also involved in the virulence of S. pneumoniae1. The prototypical RR contains a conserved regulatory domain, linked to a variable effector domain. The majority of RRs (63%) contain DNA binding effector domains. Among them, 5% interact with DNA through the unusual and recently characterized LytTR domain2. They form the AgrA/LytR RR family and regulate production of many important virulence factors. Despite their interest for drug development, no full-length RR structure has been determined yet within this family. ComE belongs to the AgrA/LytR family. We initiated a structural study of the ComE non-phosphorylable D58A mutant, and solved its X-ray 3D structure at 3.4A resolution. As expected, ComE D58A contains a conserved regulatory domain and a LytTR domain. The two domains are linked by a long non-structured linker. Interestingly, ComE D58A forms a dimer in the crystal. The regulatory domains are linked by a two-fold symmetry axis within the dimer, whereas the LytTR domains are related by both a translation and rotation (head-to-tail). This asymmetric dimer configuration is facilitated by the flexibility of the linker. The sequence of the ComE promoter is known and consists of two direct repeats. Although ComE D58A was crystallized without DNA, the dimer conformation seems to be consistent with promoter binding, which incited us to set out for a functional mechanistic study.

Structural and functional study of ComE, a key actor ofS. pneumoniaecompetence