Cell Biology

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two-component systems

The two-component signaling system comprises a histidine kinase protein that receives a signal and transmits it, via phosphorelay, to a partner response regulator protein. Such systems are found within all kingdoms of life, and more than 500 two component signal transduction systems have been identified. E. coli contains more than 30 two-component systems, controlling various aspects of cellular physiology.

The two components of these signaling systems are:
1. a sensor, and
2. a response regulator.

1. The first (sensory) component is called the transmitter domain. This and is a kinase function that phosphorylates a histidine usually located in the same protein, and so is considered an autokinase. The transmitter domain becomes a substrate for dephosphorylation by one or more "second" components.

2. The second (response regulator) component is called the receiver domain. This is a phosphatase that removes the histidyl-phosphate from the sensor by a mechanism that involves an aspartyl-phosphate intermediate in the receiver domain. The phospho-intermediate of the receiver domain induces a conformational change that regulates the functional state of an output domain, which is usually covalently linked to the receiver domain.

More detail:
In response to a signal, the histidine kinase of transmitter domain autophosphorylates (employing ATP as the phosphoryl donor ) a histidine residue in the carboxyl-terminal region of receiver domain (comprising approximately 240 amino acids), and then transfers the phosphoryl group to an aspartate residue in the amino -terminal region (comprising about 120 amino acids) of the partner response regulator protein. Thus activated, the response regulator transmits the signal to its target. The signaling pathway also includes a phosphatase that dephosphorylates the response regulator, returning it to a responsive state. The phosphatase may be the histidine kinase, the response regulator, or a separate protein.

Histidine kinases are often located in the membrane, though they may be found in the cytoplasm. Response regulators are located in the cytoplasm. The histidine kinase need not be the first protein in the signal transduction pathway to respond to the signal. In many systems, signals first interact with protein proteins other than the histidine kinase, then the stimulus is relayed to the histidine kinase. Most of the known phosphorylated response regulators stimulate or repress the transcription of specific targetted genes. ( Exceptions to this include P-CheB and P-CheY, which affect the chemotaxis machinery).

The rate at which the aspartyl-phosphate is released as inorganic phosphate – returning the response regulator to its basal state – is fine tuned to meet the needs of the specific regulation system. Thus, half lives of the phospho-intermediate vary from seconds to hours.

The two domains, transmitter and receiver, are usually found in separate polypeptides. A single transmitter may communicate with more than one receiver domain, and rarely, a single receiver domain may become phosphorylated by more than one transmitter domain. Phosphorylation may even be achieved by metabolic organic phosphates such as acetyl-phosphate or carbamoyl-phosphate.

Most gene regulation proteins are single proteins, often homodimers or homotetramers, which bound to two ligands: a. a metabolic intermediate, and b. a cis-acting gene regulation element.

Physiological Functions :
Two-component systems regulate diverse responses including
a) nutrient acquisition : nitrogen, phosphorus, carbon
b) energy metabolism : electron transport systems, uptake and catabolic machinery
c) adaptation to physical or chemical aspects of the environment : chemotaxis, pH, osmolarity, light quality
d) complex developmental pathways : sporulation, fruiting body development, swarmer cell production
e) virulence : plasmid transfer (conjugation), degredative secretions, toxin production

Examples [s] :
Some eukaryotic two-component systems (table)
With more than one protein component:
DctB/DctD - dicarboxylate transport in Rhizobium leguminosarum
EnvZ/OmpR (diagram)- osmoregulation in E. coli
NtrB/NtrC - nitrogen assimilation in a variety of bacteria
PhoR/PhoB - phosphate scavenging in E. coli
VirA/VirG - virulence by Agrobacterium tumefaciens
A 125 amino acid peptide segment is "conserved" in one subset of these gene products: OmpR, PhoB, NtrC, DctD, VirG
A "homologous" segment is present in these regulatory proteins:
Spo0A - sporulation
Spo0F - sporulation
CheY - (diagram) chemotaxis
CheB - (diagram) chemotaxis
A second, but different, "homologous" segment is present in these proteins:
EnvZ, PhoR, NtrB, DctB, VirA, and probably CheA (diagram)- chemotaxis in enteric bacteria (Che system).
NRII protein –bifunctional kinase/phosphatase regulated by PII – phosphorylates and dephosphorylates NRI, and controls the rate of transcription initiation from nitrogen-regulated promoters.
Escherichia coli BarA-UvrY two-component system is needed for efficient switching between glycolytic and gluconeogenic carbon sources. (Free Full Text Article)
H. pylori two-component systems: HP0703-HP0244 is involved in flagellar regulation; HP0166-HP0165 activates the transcription of H. pylori-specific genes in response to environmental stimuli; a set of essential target genes is regulated by HP0166. The expression of the HP0166-HP0165 two-component system is tightly balanced by a negative autoregulatory mechanism exerted by the phosphorylated response regulator.
Cyanobacterial phytochrome Cph is a light-regulated histidine kinase that mediates red, far-red reversible phosphorylation of a small response regulator, Rcp1 (response regulator for cyanobacterial phytochrome), encoded by the adjacent gene, thus implicating protein phosphorylation-dephosphorylation in the initial step of light signal transduction by phytochrome.

More links:
Arc system : Cpx system : Nar system, Nar two-component system : Summary table of 2-component signaling systems in STD bacteria : Summary of domain analysis : Domain structures of the histidine protein kinase : Domain structures of the response-regulator proteins : Browse the 2-Component systems : Pathway Two-component system : Pathway Phosphotransferase system (PTS) : Pathway Phosphatidylinositol signaling system : : Orthology Cytokines :

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