Signaling by the unique essential messenger cyclic di-AMP in Bacillus subtilis
Bacteria use so-called second messengers to transduce information on the external conditions to proteins and RNA molecules in the cell. Among all second messengers, cyclic di-AMP is unique since it is the only essential and on the other hand toxic second messenger, i.e. the bacteria are not viable without c-di-AMP, and growth is retarded upon accumulation of the molecule. We have studied the enzymes that produce and degrade c-di-AMP in B. subtilis (Fig. A). The major question of this project is the reason for the essentiality of c-di-AMP. We found that the control of potassium homoeostasis is an essential function of the nucleotide, which becomes dispensable at low potassium concentrations (see Fig. C). Fishing for c-di-AMP-binding proteins identified the target protein DarA, which we have structurally crystallized in collaboration with the Dept. of Molecular Structural Biology (Fig. D). We are now trying to identify interaction partners of DarA.
Figures. (A) The proteins that make and break c-di-AMP in B. subtilis. (B) In the cyclase CdaS, two N-terminal inhibit the activity of the compact catalytic domain. (C) A strain lacking c-di-AMP dies at elevated potassium concentrations. (D) The c-di-AMP-binding protein DarA. A ribbon view showing the trimeric organization of the protein, and a side view highlighting the possible interaction „feet“ of the protein.
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