Protein Dynamics in Phosphoryl-Transfer Signaling Mediated by Two-Component Systems

Abstract

The ability to perceive the environment, an essential attribute in living organisms, is linked to the evolution of signalling proteins that recognize specific signals and execute predetermined responses. Such proteins constitute concerted systems that can be as simple as a unique protein, able to recognize a ligand and exert a phenotypic change, or extremely complex pathways engaging dozens of different proteins which act in coordination with feedback loops and signal modulation. To understand how cells sense their surroundings and mount specific adaptive responses, we need to decipher the molecular workings of signal recognition, internalization, transfer and conversion into chemical changes inside the cell. Protein allostery and dynamics play a central role. Here, we review recent progress on the study of twocomponent systems, important signalling machineries of prokaryotes and lower eukaryotes.Such systems implicate a sensory histidine-kinase and a separate response regulator protein.Both components exploit protein flexibility to effect specific conformational rearrangements, modulating protein:protein interactions, and ultimately transmitting information accurately.Recent work has revealed how histidine-kinases switch between discrete functional states according to the presence or absence of the signal, shifting key amino acid positions that define their catalytic activity. In concert with the cognate response regulator's allosteric changes, the phosphoryl-transfer flow during the signalling process is exquisitely fine-tuned for proper specificity, efficiency and directionality.

An allosteric switch ensures efficient unidirectional information transmission by the histidine kinase DesK from Bacillus subtilis

“…5D). The pocket appears only in the phosphatase state as a consequence of how the domains are arranged in a more rigid conformation, a hallmark of the phosphatase state ( 25 ). Thus, the Q10A RR substitution would disfavor the binding interactions between RR and the phosphatase state of HK.…”

Molecular basis of unidirectional information transmission in two-component systems: lessons from the DesK-DesR thermosensor

“…On the other hand, residue Q10 RR is inserted in a pocket generated at the interface between the DHp and ATP binding domain (Figure 4c), a hallmark of the phosphatase state 36 . Remarkably, a Q10A RR mutant showed a significant increase in phosphoryltransfer reversibility, with the phosphoryl moiety more evenly distributed between the kinase and the regulator (Fig.…”