Two-component regulatory system

Last updated
Histidine kinase
Identifiers
SymbolHis_kinase
Pfam PF06580
InterPro IPR016380
OPM superfamily 281
OPM protein 5iji
His Kinase A (phospho-acceptor) domain
PDB 1joy EBI.jpg
solved structure of the homodimeric domain of EnvZ from Escherichia coli by multi-dimensional NMR.
Identifiers
SymbolHisKA
Pfam PF00512
Pfam clan CL0025
InterPro IPR003661
SMART HisKA
SCOP2 1b3q / SCOPe / SUPFAM
Histidine kinase
Identifiers
SymbolHisKA_2
Pfam PF07568
Pfam clan CL0025
InterPro IPR011495
Histidine kinase
Identifiers
SymbolHisKA_3
Pfam PF07730
Pfam clan CL0025
InterPro IPR011712
Signal transducing histidine kinase, homodimeric domain
PDB 1i5d EBI.jpg
structure of CheA domain p4 in complex with TNP-ATP
Identifiers
SymbolH-kinase_dim
Pfam PF02895
InterPro IPR004105
SCOP2 1b3q / SCOPe / SUPFAM
Histidine kinase N terminal
Identifiers
SymbolHisK_N
Pfam PF09385
InterPro IPR018984
Osmosensitive K+ channel His kinase sensor domain
Identifiers
SymbolKdpD
Pfam PF02702
InterPro IPR003852

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] Two-component systems 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] Although two-component signaling systems are found in all domains of life, they are most common by far in bacteria, particularly in Gram-negative and cyanobacteria; both histidine kinases and response regulators are among the largest gene families in bacteria. [3] They are much less common in archaea and eukaryotes; although they do appear in yeasts, filamentous fungi, and slime molds, and are common in plants, [1] two-component systems have been described as "conspicuously absent" from animals. [3]

Contents

Mechanism

Two-component systems accomplish signal transduction through the phosphorylation of a response regulator (RR) by a histidine kinase (HK). Histidine kinases are typically homodimeric transmembrane proteins containing a histidine phosphotransfer domain and an ATP binding domain, though there are reported examples of histidine kinases in the atypical HWE and HisKA2 families that are not homodimers. [4] Response regulators may consist only of a receiver domain, but usually are multi-domain proteins with a receiver domain and at least one effector or output domain, often involved in DNA binding. [3] Upon detecting a particular change in the extracellular environment, the HK performs an autophosphorylation reaction, transferring a phosphoryl group from adenosine triphosphate (ATP) to a specific histidine residue. The cognate response regulator (RR) then catalyzes the transfer of the phosphoryl group to an aspartate residue on the response regulator's receiver domain. [5] [6] This typically triggers a conformational change that activates the RR's effector domain, which in turn produces the cellular response to the signal, usually by stimulating (or repressing) expression of target genes. [3]

Many HKs are bifunctional and possess phosphatase activity against their cognate response regulators, so that their signaling output reflects a balance between their kinase and phosphatase activities. Many response regulators also auto-dephosphorylate, [7] and the relatively labile phosphoaspartate can also be hydrolyzed non-enzymatically. [1] The overall level of phosphorylation of the response regulator ultimately controls its activity. [1] [8]

Phosphorelays

Some histidine kinases are hybrids that contain an internal receiver domain. In these cases, a hybrid HK autophosphorylates and then transfers the phosphoryl group to its own 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. [9] [10] This system is called a phosphorelay. Almost 25% of bacterial HKs are of the hybrid type, as are the large majority of eukaryotic HKs. [3]

Function

Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions. [11] 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. [12] [13] The average number of two-component systems in a bacterial genome has been estimated as around 30, [14] or about 1–2% of a prokaryote's genome. [15] A few bacteria have none at all – typically endosymbionts and pathogens – and others contain over 200. [16] [17] All such systems must be closely regulated to prevent cross-talk, which is rare in vivo. [18]

In Escherichia coli , the osmoregulatory EnvZ/OmpR two-component system controls the differential expression of the outer membrane porin proteins OmpF and OmpC. [19] The KdpD sensor kinase proteins regulate the kdpFABC operon responsible for potassium transport in bacteria including E. coli and Clostridium acetobutylicum . [20] 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. [21]

Histidine kinases

Signal transducing histidine kinases are the key elements in two-component signal transduction systems. [22] [23] Examples of histidine kinases are EnvZ, which plays a central role in osmoregulation, [24] and CheA, which plays a central role in the chemotaxis system. [25] 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 to water. [26] 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. [27] [28] 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.

Evolution

The number of two-component systems present in a bacterial genome is highly correlated with genome size as well as ecological niche; bacteria that occupy niches with frequent environmental fluctuations possess more histidine kinases and response regulators. [3] [29] New two-component systems may arise by gene duplication or by lateral gene transfer, and the relative rates of each process vary dramatically across bacterial species. [30] In most cases, response regulator genes are located in the same operon as their cognate histidine kinase; [3] lateral gene transfers are more likely to preserve operon structure than gene duplications. [30]

In eukaryotes

Two-component systems are rare in eukaryotes. They appear in yeasts, filamentous fungi, and slime molds, and are relatively common in plants, but have been described as "conspicuously absent" from animals. [3] Two-component systems in eukaryotes likely originate from lateral gene transfer, often from endosymbiotic organelles, and are typically of the hybrid kinase phosphorelay type. [3] For example, in the yeast Candida albicans , genes found in the nuclear genome likely originated from endosymbiosis and remain targeted to the mitochondria. [31] Two-component systems are well-integrated into developmental signaling pathways in plants, but the genes probably originated from lateral gene transfer from chloroplasts. [3] An example is the chloroplast sensor kinase (CSK) gene in Arabidopsis thaliana , derived from chloroplasts but now integrated into the nuclear genome. CSK function provides a redox-based regulatory system that couples photosynthesis to chloroplast gene expression; this observation has been described as a key prediction of the CoRR hypothesis, which aims to explain the retention of genes encoded by endosymbiotic organelles. [32] [33]

It is unclear why canonical two-component systems are rare in eukaryotes, with many similar functions having been taken over by signaling systems based on serine, threonine, or tyrosine kinases; it has been speculated that the chemical instability of phosphoaspartate is responsible, and that increased stability is needed to transduce signals in the more complex eukaryotic cell. [3] Notably, cross-talk between signaling mechanisms is very common in eukaryotic signaling systems but rare in bacterial two-component systems. [34]

Bioinformatics

Because of their sequence similarity and operon structure, many two-component systems – particularly histidine kinases – are relatively easy to identify through bioinformatics analysis. (By contrast, eukaryotic kinases are typically easily identified, but they are not easily paired with their substrates.) [3] A database of prokaryotic two-component systems called P2CS has been compiled to document and classify known examples, and in some cases to make predictions about the cognates of "orphan" histidine kinase or response regulator proteins that are genetically unlinked to a partner. [35] [36]

Related Research Articles

Signal transduction Cascade of intracellular and molecular events for transmission/amplification of signals

Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellular response. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used. The changes elicited by ligand binding in a receptor give rise to a biochemical cascade, which is a chain of biochemical events known as a signaling pathway.

Ku (protein)

Ku is a dimeric protein complex that binds to DNA double-strand break ends and is required for the non-homologous end joining (NHEJ) pathway of DNA repair. Ku is evolutionarily conserved from bacteria to humans. The ancestral bacterial Ku is a homodimer. Eukaryotic Ku is a heterodimer of two polypeptides, Ku70 (XRCC6) and Ku80 (XRCC5), so named because the molecular weight of the human Ku proteins is around 70 kDa and 80 kDa. The two Ku subunits form a basket-shaped structure that threads onto the DNA end. Once bound, Ku can slide down the DNA strand, allowing more Ku molecules to thread onto the end. In higher eukaryotes, Ku forms a complex with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to form the full DNA-dependent protein kinase, DNA-PK. Ku is thought to function as a molecular scaffold to which other proteins involved in NHEJ can bind, orienting the double-strand break for ligation.

Protein-glutamate methylesterase

In enzymology, a protein-glutamate methylesterase (EC 3.1.1.61) is an enzyme that catalyzes the chemical reaction

Autoinducers are signaling molecules that are produced in response to changes in cell-population density. As the density of quorum sensing bacterial cells increases so does the concentration of the autoinducer. Detection of signal molecules by bacteria acts as stimulation which leads to altered gene expression once the minimal threshold is reached. Quorum sensing is a phenomenon that allows both Gram-negative and Gram-positive bacteria to sense one another and to regulate a wide variety of physiological activities. Such activities include symbiosis, virulence, motility, antibiotic production, and biofilm formation. Autoinducers come in a number of different forms depending on the species, but the effect that they have is similar in many cases. Autoinducers allow bacteria to communicate both within and between different species. This communication alters gene expression and allows bacteria to mount coordinated responses to their environments, in a manner that is comparable to behavior and signaling in higher organisms. Not surprisingly, it has been suggested that quorum sensing may have been an important evolutionary milestone that ultimately gave rise to multicellular life forms.

Histidine kinase

Histidine kinases (HK) are multifunctional, and in non-animal kingdoms, typically transmembrane, proteins of the transferase class of enzymes that play a role in signal transduction across the cellular membrane. The vast majority of HKs are homodimers that exhibit autokinase, phosphotransfer, and phosphatase activity. HKs can act as cellular receptors for signaling molecules in a way analogous to tyrosine kinase receptors (RTK). Multifunctional receptor molecules such as HKs and RTKs typically have portions on the outside of the cell that bind to hormone- or growth factor-like molecules, portions that span the cell membrane, and portions within the cell that contain the enzymatic activity. In addition to kinase activity, the intracellular domains typically have regions that bind to a secondary effector molecule or complex of molecules that further propagate signal transduction within the cell. Distinct from other classes of protein kinases, HKs are usually parts of a two-component signal transduction mechanisms in which HK transfers a phosphate group from ATP to a histidine residue within the kinase, and then to an aspartate residue on the receiver domain of a response regulator protein. More recently, the widespread existence of protein histidine phosphorylation distinct from that of two-component histidine kinases has been recognised in human cells. In marked contrast to Ser, Thr and Tyr phosphorylation, the analysis of phosphorylated Histidine using standard biochemical and mass spectrometric approaches is much more challenging, and special procedures and separation techniques are required for their preservation alongside classical Ser, Thr and Tyr phosphorylation on proteins isolated from human cells.

Phosphocarrier protein

Phosphocarrier HPr protein is a small cytoplasmic protein that is a component of the phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS).

Methyl-accepting chemotaxis proteins

The Methyl-accepting chemotaxis proteins are a family of transmembrane receptors that mediate chemotactic response in certain enteric bacteria, such as Salmonella typhimurium and Escherichia coli. These methyl-accepting chemotaxis receptors are one of the first components in the sensory excitation and adaptation responses in bacteria, which act to alter swimming behaviour upon detection of specific chemicals. Use of the MCP allows bacteria to detect concentrations of molecules in the extracellular matrix so that the bacteria may smooth swim or tumble accordingly. If the bacterium detects rising levels of attractants (nutrients) or declining levels of repellents (toxins), the bacterium will continue swimming forward, or smooth swimming. If the bacterium detects declining levels of attractants or rising levels of repellents, the bacterium will tumble and re-orient itself in a new direction. In this manner, a bacterium may swim towards nutrients and away from toxins

The CHASE domain is an extracellular protein domain, which is found in transmembrane receptor from bacteria, lower eukaryotes and plants. It has been named CHASE because of its presence in diverse receptor-like proteins with histidine kinase and nucleotide cyclase domains. The CHASE domain is 200-230 amino acids long and always occurs N-terminally in extracellular or periplasmic locations, followed by an intracellular tail housing diverse enzymatic signalling domains such as histidine kinase, adenyl cyclase, GGDEF-type nucleotide cyclase and EAL-type phosphodiesterase domains, as well as non-enzymatic domains such PAS, GAF, phosphohistidine and response regulatory domains. The CHASE domain is predicted to bind diverse low molecular weight ligands, such as the cytokinin-like adenine derivatives or peptides, and mediate signal transduction through the respective receptors.

Sda protein domain

In molecular biology, the protein domain Sda is short for suppressor of dnaA or otherwise known as sporulation inhibitor A. It is found only in bacteria. This protein domain is highly important to cell survival. When starved of nutrients, the cell is under extreme stress so undergoes a series of reactions to increase the chances of survival. One method is to form endospores which can withstand a large amount of environmental pressure. Sda protein domain is a checkpoint which prevents the formation of spores. The Sda domain affects cell signalling. It prevents the cell communicating the stress that it is under, which is crucial if the cell is to survive.

Ars operon

In molecular biology, the ars operon is an operon found in several bacterial taxon. It is required for the detoxification of arsenate, arsenite, and antimonite. This system transports arsenite and antimonite out of the cell. The pump is composed of two polypeptides, the products of the arsA and arsB genes. This two-subunit enzyme produces resistance to arsenite and antimonite. Arsenate, however, must first be reduced to arsenite before it is extruded. A third gene, arsC, expands the substrate specificity to allow for arsenate pumping and resistance. ArsC is an approximately 150-residue arsenate reductase that uses reduced glutathione (GSH) to convert arsenate to arsenite with a redox active cysteine residue in the active site. ArsC forms an active quaternary complex with GSH, arsenate, and glutaredoxin 1 (Grx1). The three ligands must be present simultaneously for reduction to occur.

Flagellar motor switch

In molecular biology, the flagellar motor switch is a protein complex. In Escherichia coli and Salmonella typhimurium it regulates the direction of flagellar rotation and hence controls swimming behaviour. The switch is a complex apparatus that responds to signals transduced by the chemotaxis sensory signalling system during chemotactic behaviour. CheY, the chemotaxis response regulator, is believed to act directly on the switch to induce a switch in the flagellar motor direction of rotation.

Ferric uptake regulator family

In molecular biology, the ferric uptake regulator family is a family of bacterial proteins involved in regulating metal ion uptake and in metal homeostasis. The family is named for its founding member, known as the ferric uptake regulator or ferric uptake regulatory protein (Fur). Fur proteins are responsible for controlling the intracellular concentration of iron in many bacteria. Iron is essential for most organisms, but its concentration must be carefully managed over a wide range of environmental conditions; high concentrations can be toxic due to the formation of reactive oxygen species.

LuxR-type DNA-binding HTH domain

In molecular biology, the LuxR-type DNA-binding HTH domain is a DNA-binding, helix-turn-helix (HTH) domain of about 65 amino acids. It is present in transcription regulators of the LuxR/FixJ family of response regulators. The domain is named after Vibrio fischeri luxR, a transcriptional activator for quorum-sensing control of luminescence. LuxR-type HTH domain proteins occur in a variety of organisms. The DNA-binding HTH domain is usually located in the C-terminal region of the protein; the N-terminal region often containing an autoinducer-binding domain or a response regulatory domain. Most luxR-type regulators act as transcription activators, but some can be repressors or have a dual role for different sites. LuxR-type HTH regulators control a wide variety of activities in various biological processes.

EnvZ/OmpR is a two-component regulatory system widely distributed in bacteria and particularly well characterized in Escherichia coli. Its function is in osmoregulation, responding to changes in environmental osmolality by regulating the expression of the outer membrane porins OmpF and OmpC. EnvZ is a histidine kinase which also possesses a cytoplasmic osmosensory domain, and OmpR is its corresponding response regulator protein.

Response regulator

A response regulator is a protein that mediates a cell's response to changes in its environment as part of a two-component regulatory system. Response regulators are coupled to specific histidine kinases which serve as sensors of environmental changes. Response regulators and histidine kinases are two of the most common gene families in bacteria, where two-component signaling systems are very common; they also appear much more rarely in the genomes of some archaea, yeasts, filamentous fungi, and plants. Two-component systems are not found in metazoans.

In molecular biology, the HAMP domain is an approximately 50-amino acid alpha-helical region that forms a dimeric, four-helical coiled coil. It is found in bacterial sensor and chemotaxis proteins and in eukaryotic histidine kinases. The bacterial proteins are usually integral membrane proteins and part of a two-component signal transduction pathway. One or several copies of the HAMP domain can be found in association with other domains, such as the histidine kinase domain, the bacterial chemotaxis sensory transducer domain, the PAS repeat, the EAL domain, the GGDEF domain, the protein phosphatase 2C-like domain, the guanylate cyclase domain, or the response regulatory domain. In its most common setting, the HAMP domain transmits conformational changes in periplasmic ligand-binding domains to cytoplasmic signalling kinase and methyl-acceptor domains and thus regulates the phosphorylation or methylation activity of homodimeric receptors.

Histidine phosphotransfer domain

Histidine phosphotransfer domains and histidine phosphotransferases are protein domains involved in the "phosphorelay" form of two-component regulatory systems. These proteins possess a phosphorylatable histidine residue and are responsible for transferring a phosphoryl group from an aspartate residue on an intermediate "receiver" domain, typically part of a hybrid histidine kinase, to an aspartate on a final response regulator.

A cytokinin signaling and response regulator protein is a plant protein that is involved in a two step cytokinin signaling and response regulation pathway.

Accessory gene regulator (agr) is a complex 5 gene locus that is a global regulator of virulence in Staphylococcus aureus. It encodes a two-component transcriptional quorum-sensing (QS) system activated by an autoinducing, thiolactone-containing cyclic peptide (AIP).

Ethylene signaling pathway

Ethylene signaling pathway is a signal transduction in plant cells to regulate important growth and developmental processes. Acting as a plant hormone, the gas ethylene is responsible for promoting the germination of seeds, ripening of fruits, the opening of flowers, the abscission of leaves and stress responses. It is the simplest alkene gas and the first gaseous molecule discovered to function as a hormone.

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