Bacterial cyclic di-AMP second-messenger signalling

A bacterial second-messenger motif in which diadenylate cyclases synthesize cyclic di-AMP, phosphodiesterases control its turnover, and protein receptors couple ligand occupancy to physiology. The characterized Bacillota implementations combine membrane CdaA/DacA or cytoplasmic DisA cyclases with GdpP or PgpH hydrolysis to pApA. A separable Pde2 clearance step converts pApA to AMP and can relieve feedback inhibition of GdpP. Receptor outputs differ: Ktr/CabP and KdpD restrain potassium uptake, OpuCA is associated with reduced osmolyte uptake, KhtT stimulates potassium export through ligand-dependent release of restraint, and apo-DarB regulates metabolic enzymes. PII-like DarA/PstA proteins bind the messenger but their direct targets remain unresolved.

Boundary: synthesis, messenger turnover and direct protein-receptor engagement in the sampled Bacillota implementations. The taxon context is an explicit envelope for these representatives, not a claim that c-di-AMP is absent outside Bacillota or that every member of the phylum has every branch. All representative strain identities are retained. A family classification alone is not evidence that all family members bind c-di-AMP: KdpD and OpuCA selectors are functionally restricted subclasses. The RCK_C domain spans unrelated transporter-associated architectures, which are separate branches here. The motif requires synthesis, a modeled c-di-AMP-opening enzyme and at least one receptor. pApA clearance is an optional extension because its experimentally detailed GdpP feedback loop is a species-specific implementation, not a demonstrated universal requirement for reception. This representation is a capacity model, not a viability prediction, concentration simulation or claim that the illustrated panel exhausts all c-di-AMP pathways. A partial representative panel does not establish a complete native circuit. CdaS/CdaM cyclases, direct metabolic/transport receptors such as PycA/KimA, RNA riboswitches and non-Bacillota degradative routes are outside this sampled implementation; they are known biology, not knowledge gaps. The downstream pumps and enzymes are outside the receptor boundary. KdpD/KdpE and KdpFABC are represented in MODULE:bacterial_kdp_potassium_homeostasis; host STING reception belongs to MODULE:cgas_sting_signaling. Do not infer that every receptor inhibits uptake or that decreasing receptor occupancy has the same physiological sign on every branch. KhtT export activation is measured, while the accessible CpaA primary abstract establishes antiporter modulation without an exact ion/sign assignment. KdpD expression effects do not by themselves establish autokinase inhibition. OpuCA's isolated ATPase was weak and ligand-insensitive in the cited study, so the coupling mechanism remains unresolved. GO:0106408 denotes diadenylate, not adenylate, cyclase; GO:0106409 opens c-di-AMP to pApA. Both definitions and GO:0180001 binding were checked in QuickGO. GO:0034611 is obsolete. The pApA step uses a proposed substrate-specific activity rather than substituting the cyclic-substrate GO activity. In vitro Pde2 c-di-AMP turnover is not treated as a proven physiological bypass. ATPase and heme effects in Bacillus GdpP are not generalized to the S. aureus protein. No upstream issue has been filed by this audit.