Two-component regulatory system

His Kinase A (phospho-acceptor) domain
solution structure of the homodimeric domain of envz from escherichia coli by multi-dimensional nmr.
Identifiers
Symbol	HisKA
Pfam	PF00512
Pfam clan	CL0025
InterPro	IPR003661
SMART	HisKA
SCOP	1b3q
SUPERFAMILY	1b3q
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Signal transducing histidine kinase, homodimeric domain
structure of chea domain p4 in complex with tnp-atp
Identifiers
Symbol	H-kinase_dim
Pfam	PF02895
InterPro	IPR004105
SCOP	1b3q
SUPERFAMILY	1b3q
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

In the field of molecular biology, a two-component regulatory system serves as a basic stimulus-response coupling mechanism to allow organisms to sense and respond to changes in many different environmental conditions.^[1] They typically consist of a membrane-bound histidine kinase that senses a specific environmental stimulus and a corresponding response regulator that mediates the cellular response, mostly through differential expression of target genes.^[2] Two component signaling systems are widely occurring in prokaryotes whereas only a few two-component systems have been identified in eukaryotic organisms.^[1]

Mechanism of action

Signal transduction occurs through the transfer of phosphoryl groups from adenosine triphosphate (ATP) to a specific histidine residue in the histidine kinases (HK). This is an autophosphorylation reaction. The response regulators (RRs) were shown to be phosphorylated on an aspartate residue and to be protein phosphatases for the histidine kinases.^[3] The response regulators are therefore enzymes with a covalent intermediate that alters response-regulator output function.^[4] Phosphorylation causes the response regulator's conformation to change, usually activating an attached output domain, which then leads to the stimulation (or repression) of expression of target genes. The level of phosphorylation of the response regulator controls its activity.^[5][6] Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.

Function

Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions.^[7] Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk.^[8] These pathways have been adapted to respond to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, temperature, chemoattractants, pH and more.^[9][10] In Escherichia coli, the EnvZ/OmpR osmoregulation system controls the differential expression of the outer membrane porin proteins OmpF and OmpC.^[11] The KdpD sensor kinase proteins regulate the kdpFABC operon responsible for potassium transport in bacteria including E. coli and Clostridium acetobutylicum.^[12] The N-terminal domain of this protein forms part of the cytoplasmic region of the protein, which may be the sensor domain responsible for sensing turgor pressure.^[13]

Phospho-relay system

A variant of the two-component system is the phospho-relay system. Here a hybrid HK autophosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response.^[14][15]

Histidine kinases

Signal transducing histidine kinases are the key elements in two-component signal transduction systems.^[16][17] Examples of histidine kinases are EnvZ, which plays a central role in osmoregulation,^[18] and CheA, which plays a central role in the chemotaxis system.^[19] Histidine kinases usually have an N-terminal ligand-binding domain and a C-terminal kinase domain, but other domains may also be present. The kinase domain is responsible for the autophosphorylation of the histidine with ATP, the phosphotransfer from the kinase to an aspartate of the response regulator, and (with bifunctional enzymes) the phosphotransfer from aspartyl phosphate back to ADP or to water.^[20] The kinase core has a unique fold, distinct from that of the Ser/Thr/Tyr kinase superfamily.

HKs can be roughly divided into two classes: orthodox and hybrid kinases.^[21][22] Most orthodox HKs, typified by the E. coli EnvZ protein, function as periplasmic membrane receptors and have a signal peptide and transmembrane segment(s) that separate the protein into a periplasmic N-terminal sensing domain and a highly conserved cytoplasmic C-terminal kinase core. Members of this family, however, have an integral membrane sensor domain. Not all orthodox kinases are membrane bound, e.g., the nitrogen regulatory kinase NtrB (GlnL) is a soluble cytoplasmic HK.^[6] Hybrid kinases contain multiple phosphodonor and phosphoacceptor sites and use multi-step phospho-relay schemes instead of promoting a single phosphoryl transfer. In addition to the sensor domain and kinase core, they contain a CheY-like receiver domain and a His-containing phosphotransfer (HPt) domain.

See also

• P2CS database

References

This article incorporates text from the public domain Pfam and InterPro IPR011712

This article incorporates text from the public domain Pfam and InterPro IPR010559

This article incorporates text from the public domain Pfam and InterPro IPR003661

This article incorporates text from the public domain Pfam and InterPro IPR011495

This article incorporates text from the public domain Pfam and InterPro IPR004105

This article incorporates text from the public domain Pfam and InterPro IPR011126

This article incorporates text from the public domain Pfam and InterPro IPR003852