Table 2.
Regulatory domains of c-di-AMP receptorsa
| Receptor typeb | Characterized examples | |||
|---|---|---|---|---|
| Organismc, accession numbers | Structure, PDB coded | Estimated Kd, μMe | References | |
| Riboswitch | ||||
| ydaO (potE) | Bacillus subtilis | 4W90 | <0.1 nM, 0.7 nM | (100,116) |
| Bacillus subtilis | 7.4 ± 2.2 nM | (117) | ||
| Nostoc punctiforme | – | 30 nM | (100) | |
| Syntrophus aciditrophicus | – | 0.55 nM | (100) | |
| Clostridium acetobutylicum | – | 1 nM | (100) | |
| Thermovirga lienii | 4QK9 | 300 ± 166 nM | (117) | |
| Thermoanaerobacter pseudethanolicus | 4QK8 | – | (117) | |
| Caldanaerobacter subterraneus | 4QLN | – | (118) | |
| Protein (domain) name | ||||
| RCK_C (TrkA_C) domain, PF02080 | ||||
| K+ uptake protein TrkA, COG0569 | S. aureus (ABD22474) | 4XTT | 0.043 ± 0.016; 0.064 ± 0.003; 0.369 ± 0.044 | (57,111) |
| B. subtilis (CAB15087, BAA07051) | – | – | (66) | |
| L. monocytogenes (CAC99101) | – | 1.2 ± 0.2 | (62) | |
| M. pneumoniae (AAB96028) | – | – | (33) | |
| S. agalactiae (CAD47298, CAD47337) | – | – | (88) | |
| S. mutans (AAN59208, AAN59343) | – | 7.8 ± 0.3 | (67) | |
| S. pneumoniae (ABJ54144) | 0.15 | (58) | ||
| Na+/H+ and K+/H+ antiporter CpaA, COG0475 | S. aureus (ABD21176) | 5F29 | 9.0 | (57,99) |
| B. subtilis (CAB13021) | – | – | (66) | |
| K+/H+ antiporter subunit KhtT, COG0490 | B. subtilis (CAB12826, CAB14723) | – | – | (66) |
| Transcriptional regulator BusR | L. lactis R (CAL97640) | – | 10 | (65) |
| S. agalactiae (CAD46860) | (88) | |||
| CBS pair (PF00571) | ||||
| Carnitine transporter subunit OpuCA, COG1125 | L. monocytogenes (CAC99506) | 5KS7 | 1.2 | (63) |
| E. faecalis (AAO80496) | – | 6 | (63) | |
| S. aureus (AAW38543) | – | 2.46 ± 0.14 | (64) | |
| S. agalactiae (CAD45880) | – | – | (88) | |
| B. subtilis (CAB15388) | – | – | (66) | |
| Mg2+ transporter MgtE, COG2239 | B. subtilis (CAB13187) | – | – | (66) |
| Stand-alone CBS domain, COG0517 | B. subtilis (CAB13286) | – | 1.8 ± 0.2 | (66) |
| L. monocytogenes (CAC98632, CAC99087) | – | 2.2 ± 0.4 | (69) | |
| USP domain | ||||
| K+-sensing histidine kinase KdpD, COG2205 | S. aureus (AAW37032, CAG39096) | – | 2.01 ± 0.18 | (57,59) |
| L. monocytogenes (CAD00892) | – | – | (62,63) | |
| S. elongatus (ABB57759) | – | – | (72) | |
| K+ uptake protein KimA, COG0531, PF13520 | B. subtilis (CAB12239) | – | – | (60,66) |
| L. monocytogenes (CAD00208) | – | – | (62) | |
| S. aureus (AAW38535) | – | – | (66) | |
| KupAC domain | ||||
| K+ transporter Kup/TrkD, COG3158, PF02705 | L. lactis (AAK04721, AAK04722, CAL97188) | – | – | (65,82) |
| Other receptors | ||||
| PII-like protein DarA/PstA, COG3870, PF06153 | L. monocytogenes (CAD00905) | 4RWW | 1.4 | (69,86) |
| B. subtilis (CAB11805) | 4RLE | 0.64, 1.3 ± 0.07 | (84) | |
| S. aureus (AAW37644) | 4WK1, 4D3H | 0.109 | (85,87) | |
| Pyruvate carboxylase, COG1038 | L. monocytogenes (CAC99150), | 4QSH | 8 ± 0.2 | (69) |
| L. lactis (AAK04767) | 5VYZ | – | (139) | |
| E. faecalis (AAO82174) | – | – | (69) | |
| Transcriptional regulators | ||||
| M. smegmatis DarR (ABK70852) | – | 2.3 ± 0.5 | (71) | |
| L. monocytogenes NrdR (CAC99640) | – | – | (69) | |
| Eukaryotic proteins | ||||
| STING | Sea anemone | 5CFN | – | (113) |
| Mouse | 4YP1 | 1.85 | (99) | |
| Pig | 6IYF | – | (112) | |
| Human | 6CFF | – | (140) | |
| DDX41 | Mouse | – | – | (103) |
| RECON | Mouse | 5UXF | 0.087 | (104) |
| ERAdP | Mouse | – | 0.076 | (105) |
aThe L. monocytogenes c-di-AMP phosphodiesterases PdeA (lmo0052) and PgpH (lmo1466), identified as c-di-AMP binders structurally, by binding to the c-di-AMP-linked Sepharose beads, and in the DRaCALA assay (42,69) are omitted here but listed in Table 1. The ClpC (lmo0232), CtaP (lmo0135), OppA (lmo2196), Ndh (lmo2638) and Adh (lmo1634) proteins, identified as potential c-di-AMP binders in the DRaCALA assay (69) are not listed as their interaction with c-di-AMP is likely indirect.
bThe protein and domain names are taken from Pfam (5) and/or the COG database (6). Sequence alignments and sequence logos of the newly described KimAC and KupAC domains are provided in Figures S3 and S4 in the Supplementary Materials.
cFor the full names of organisms, see the text or the respective GenBank or UniProt entries.
dWhere available, protein structures listed are those in complex with bound c-di-AMP.
e K d values are in nM for the riboswitches and in μM for protein receptors.