# The World of Cyclic Dinucleotides in Bacterial Behavior
## 3 Cyclic Dinucleotide Receptors
Another protein that interacts with c-di-AMP by a poorly understood mechanism is KdpD/KdpE that controls the potassium uptake in situations where the potassium concentrations are extremely low and other uptake systems wouldn't be enough to give the cell all potassium it requires. In _Escherichia coli_, there are three systems responsible for potassium uptake, namely, Trk, Kdp, and Kup. In the case of Trk system, four genes are constitutively expressed and TrkA is the predominant potassium transporter at neutral pH. The Kdp-ATPase system is induced at low potassium concentrations and under conditions of osmotic stress. The Kup, formerly TrkD, is activated when TrkA and Kdp activities are not sufficient [131; 132; 133]. In _Bacillus subtilis_, a novel high-affinity transporter KimA (formerly YdaO) has recently been characterized and the expression of KimA and KtrAB is negatively regulated by c-di-AMP riboswitches [28]. When the concentration of potassium is high in the cell, the concentration of c-di-AMP increases inhibiting potassium uptake by two ways, by binding to c-di-AMP riboswitches that will avoid the expression of proteins involved in transport, and by direct interactions with regulatory subunits of KtrAB and KtrCD causing the inhibition of potassium transport [134]. A similar process seems to happen in _Staphylococcus aureus_, where c-di-AMP binds to the KtrA protein and to the universal stress protein (USP) domain of the KdpD sensor kinase inhibiting the expression of Kdp potassium transporter components. In this manner, c-di-AMP appears to be a negative regulator of potassium uptake in different Gram-positive bacteria [60; 134]. One of the most well understood receptors for c-di-AMP is KtrA, which binds c-di-AMP through its C-terminal domain (RCK_C or TrkA_C) to cause inactivation of the KtrA function (Table 1). c-di-AMP binds to the interface of the KtrA homodimer, and the residues involved in the ligand interaction are described in Table 1. Another c-di-AMP receptor is the c-di-AMP receptor domain (PF06153) of the PII-like signal transduction protein, PstA. PstA is a homotrimer and, in each protein interface, one c-di-AMP molecule is bound. The residues involved in ligand binding in PstA are also described in Table 1.  
c-di-AMP is also related with negative control of aspartate and pyruvate pools in _Lactococcus lactis_ by a pyruvate carboxylase, LIPC protein, and _Listeria monocytogenes_ pyruvate carboxylase, LmPC protein, respectively. In both cases, c-di-AMP binds to the pyruvate carboxylase domain (HMGL-like domain in the Pfam) (Table 1). LIPC forms a tetramer and each c-di-AMP molecule binds the protein dimer interface at the carboxyltransferase (CT) domain in a binding site pocket containing residues that are poorly conserved among pyruvate carboxylases [135]. The huge repertoire of CDN receptors demonstrates the complexity of CDN signaling networks in bacteria. Additionally, CDNs may regulate different bacterial behaviors at different speeds through regulation of gene transcription by transcriptional factors, protein translation by riboswitches, and directly by regulating the function of different classes of protein. \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Receptor Class** & **Organism** & **Receptor Function** & **Ligand Binding Site** & **Ref. ** \\ (Pfam/Rfam) & **(PDBID)** & & **3-5-5-di-GMP** & \\ \hline \multirow{8}{*}{_Sus scra_} & \multirow{8}{*}{_Homo sapiens_ (4 EF4, 4 EMT, 6 RM0, 6886, 4F9G, 4F5D, 4F5Y)_} & Members of Transmembrane Protein 173 (TMEM173) family, also known as Stimulator of Interferon Genes (STING), are an important component of the immune system. STING proteins are responsible for regulating the induction of type I interferon via activation of INF-\(\beta\) gene transcription. & STING proteins interact with c-di-GMP at the protein dimer interface in a perfectly symmetrical manner increasing the homodimer stability.