cAMP receptor proteins in mycobacteria

Cyclic adenosine monophosphate (cAMP) signaling is a major regulatory system in mycobacteria, and the cAMP receptor protein (CRP) serves as its principal transcriptional effector. In Mycobacterium tuberculosis, CRP controls a broad regulon associated with metabolic adaptation, respiration, cell envelope-associated processes, dormancy-related resuscitation, and virulence. Structural and biophysical studies have demonstrated that mycobacterial CRPs differ from the classical Escherichia coli paradigm: apo-CRP adopts restrained or asymmetric conformations, whereas cAMP binding promotes a more symmetric, DNA-binding-competent state and enhances the specificity of CRP-DNA interactions. In Mycobacterium smegmatis, the major paralog Crp1 (MSMEG_6189) regulates metabolic and respiratory adaptation, oxidative stress defense, and isoniazid susceptibility, whereas Crp2 (MSMEG_0539) appears to play a more limited or subsidiary role. Recent findings further reveal that CRP activity is modulated by lysine acetylation, cooperative promoter recruitment with the virulence-associated response regulator PhoP, and respiratory inhibition-induced increases in intracellular cAMP, thereby linking metabolic and respiratory status to adaptive and virulence-associated gene regulation. This review summarizes the structure, allosteric regulation, regulon, and physiological functions of mycobacterial CRPs, highlighting their role as central integrators of cAMP signaling, respiratory and metabolic state, persistence-associated physiology, and antibiotic susceptibility.