Two-component systems reprogramme diverse aspects of microbial physiology in response to environmental cues. Canonical systems are composed of a transmembrane sensor histidine kinase and its cognate ...response regulator. They catalyse three reactions: autophosphorylation of the histidine kinase, transfer of the phosphoryl group to the regulator and dephosphorylation of the phosphoregulator. Elucidating signal transduction between sensor and output domains is highly challenging given the size, flexibility and dynamics of histidine kinases. However, recent structural work has provided snapshots of the catalytic mechanisms of the three enzymatic reactions and described the conformation and dynamics of the enzymatic moiety in the kinase-competent and phosphatase-competent states. Insight into signalling mechanisms across the membrane is also starting to emerge from new crystal structures encompassing both sensor and transducer domains of sensor histidine kinases. In this Progress article, we highlight such important advances towards understanding at the molecular level the signal transduction mechanisms mediated by these fascinating molecular machines.
L-histidine (HIS) is an essential amino acid with unique roles in proton buffering, metal ion chelation, scavenging of reactive oxygen and nitrogen species, erythropoiesis, and the histaminergic ...system. Several HIS-rich proteins (e.g., haemoproteins, HIS-rich glycoproteins, histatins, HIS-rich calcium-binding protein, and filaggrin), HIS-containing dipeptides (particularly carnosine), and methyl- and sulphur-containing derivatives of HIS (3-methylhistidine, 1-methylhistidine, and ergothioneine) have specific functions. The unique chemical properties and physiological functions are the basis of the theoretical rationale to suggest HIS supplementation in a wide range of conditions. Several decades of experience have confirmed the effectiveness of HIS as a component of solutions used for organ preservation and myocardial protection in cardiac surgery. Further studies are needed to elucidate the effects of HIS supplementation on neurological disorders, atopic dermatitis, metabolic syndrome, diabetes, uraemic anaemia, ulcers, inflammatory bowel diseases, malignancies, and muscle performance during strenuous exercise. Signs of toxicity, mutagenic activity, and allergic reactions or peptic ulcers have not been reported, although HIS is a histamine precursor. Of concern should be findings of hepatic enlargement and increases in ammonia and glutamine and of decrease in branched-chain amino acids (valine, leucine, and isoleucine) in blood plasma indicating that HIS supplementation is inappropriate in patients with liver disease.
Two-component systems (TCS) comprising sensor histidine kinases and response regulator proteins are among the most important players in bacterial and archaeal signal transduction and also occur in ...reduced numbers in some eukaryotic organisms. Given their importance to cellular survival, virulence, and cellular development, these systems are among the most scrutinized bacterial proteins. In the recent years, a flurry of bioinformatics, genetic, biochemical, and structural studies have provided detailed insights into many molecular mechanisms that underlie the detection of signals and the generation of the appropriate response by TCS. Importantly, it has become clear that there is significant diversity in the mechanisms employed by individual systems. This review discusses the current knowledge on common themes and divergences from the paradigm of TCS signaling. An emphasis is on the information gained by a flurry of recent structural and bioinformatics studies.
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•TCS are the most prevalent signal transduction pathways in bacteria.•A flurry of new structures have contributed to our understanding of these systems.•This review discusses common features, paradigms, and deviations from the paradigm.
WalKR (YycFG) is the only essential two-component regulator in the human pathogen Staphylococcus aureus. WalKR regulates peptidoglycan synthesis, but this function alone does not explain its ...essentiality. Here, to further understand WalKR function, we investigate a suppressor mutant that arose when WalKR activity was impaired; a histidine to tyrosine substitution (H271Y) in the cytoplasmic Per-Arnt-Sim (PAS
) domain of the histidine kinase WalK. Introducing the WalK
mutation into wild-type S. aureus activates the WalKR regulon. Structural analyses of the WalK PAS
domain reveal a metal-binding site, in which a zinc ion (Zn
) is tetrahedrally-coordinated by four amino acids including H271. The WalK
mutation abrogates metal binding, increasing WalK kinase activity and WalR phosphorylation. Thus, Zn
-binding negatively regulates WalKR. Promoter-reporter experiments using S. aureus confirm Zn
sensing by this system. Identification of a metal ligand recognized by the WalKR system broadens our understanding of this critical S. aureus regulon.
Cytosolic hybrid histidine kinases (HHKs) constitute major signaling nodes that control various biological processes, but their input signals and how these are processed are largely unknown. In ...Caulobacter crescentus, the HHK ShkA is essential for accurate timing of the G1-S cell cycle transition and is regulated by the corresponding increase in the level of the second messenger c-di-GMP. Here, we use a combination of X-ray crystallography, NMR spectroscopy, functional analyses, and kinetic modeling to reveal the regulatory mechanism of ShkA. In the absence of c-di-GMP, ShkA predominantly adopts a compact domain arrangement that is catalytically inactive. C-di-GMP binds to the dedicated pseudoreceiver domain Rec1, thereby liberating the canonical Rec2 domain from its central position where it obstructs the large-scale motions required for catalysis. Thus, c-di-GMP cannot only stabilize domain interactions, but also engage in domain dissociation to allosterically invoke a downstream effect. Enzyme kinetics data are consistent with conformational selection of the ensemble of active domain constellations by the ligand and show that autophosphorylation is a reversible process.
Histidine is a nutritionally essential amino acid with many recognized benefits to human health, while circulating concentrations of histidine decline in pathologic conditions e.g., chronic ...obstructive pulmonary disease (COPD) and chronic kidney disease (CKD). The purpose of this review is to examine the existing literature regarding the benefits of histidine intake, the adverse effects of excess histidine, and the upper tolerance level for histidine. Supplementation with doses of 4.0–4.5 g histidine/d and increased dietary histidine intake are associated with decreased BMI, adiposity, markers of glucose homeostasis (e.g., HOMA-IR, fasting blood glucose, 2-h postprandial blood glucose), proinflammatory cytokines, and oxidative stress. It is unclear from the limited number of studies in humans whether the improvements in glucoregulatory markers, inflammation, and oxidative stress are due to reduced BMI and adiposity, increased carnosine (a metabolic product of histidine with antioxidant effects), or both. Histidine intake also improves cognitive function (e.g., reduces appetite, anxiety, and stress responses and improves sleep) potentially through the metabolism of histidine to histamine; however, this relation is ambiguous in humans. At high intakes of histidine (>24 g/d), studies report adverse effects of histidine such as decreased serum zinc and cognitive impairment. There is limited research on the effects of histidine intake at doses between 4.5 and 24 g/d, and thus, a tolerable upper level has not been established. Determining tolerance to histidine supplementation has been limited by small sample sizes and, more important, a lack of a clear biomarker for histidine supplementation. The U-shaped curve of circulating zinc concentrations with histidine supplementation could be exploited as a relevant biomarker for supplemental histidine tolerance. Histidine is an important amino acid and may be necessary as a supplement in some populations; however, gaps in knowledge, which this review highlights, need to be addressed scientifically.
Two‐component systems (TCS) constitute the predominant means by which prokaryotes read out and adapt to their environment. Canonical TCSs comprise a sensor histidine kinase (SHK), usually a ...transmembrane receptor, and a response regulator (RR). In signal‐dependent manner, the SHK autophosphorylates and in turn transfers the phosphoryl group to the RR which then elicits downstream responses, often in form of altered gene expression. SHKs also catalyze the hydrolysis of the phospho‐RR, hence, tightly adjusting the overall degree of RR phosphorylation. Photoreceptor histidine kinases are a subset of mostly soluble, cytosolic SHKs that sense light in the near‐ultraviolet to near‐infrared spectral range. Owing to their experimental tractability, photoreceptor histidine kinases serve as paradigms and provide unusually detailed molecular insight into signal detection, decoding, and regulation of SHK activity. The synthesis of recent results on receptors with light‐oxygen‐voltage, bacteriophytochrome and microbial rhodopsin sensor units identifies recurring, joint signaling strategies. Light signals are initially absorbed by the sensor module and converted into subtle rearrangements of α helices, mostly through pivoting and rotation. These conformational transitions propagate through parallel coiled‐coil linkers to the effector unit as changes in left‐handed superhelical winding. Within the effector, subtle conformations are triggered that modulate the solvent accessibility of residues engaged in the kinase and phosphatase activities. Taken together, a consistent view of the entire trajectory from signal detection to regulation of output emerges. The underlying allosteric mechanisms could widely apply to TCS signaling in general.
Response regulators function as the output components of two-component systems, which couple the sensing of environmental stimuli to adaptive responses. Response regulators typically contain ...conserved receiver (REC) domains that function as phosphorylation-regulated switches to control the activities of effector domains that elicit output responses. This modular design is extremely versatile, enabling different regulatory strategies tuned to the needs of individual signaling systems. This review summarizes structural features that underlie response regulator function. An abundance of atomic resolution structures and complementary biochemical data have defined the mechanisms for response regulator enzymatic activities, revealed trends in regulatory strategies utilized by response regulators of different subfamilies, and provided insights into interactions of response regulators with their cognate histidine kinases. Among the hundreds of thousands of response regulators identified, variations abound. This article provides a framework for understanding structural features that enable function of canonical response regulators and a basis for distinguishing noncanonical configurations.
•l-Histidine (His), imidazole (Imi) and l-carnosine (Car) increased solubility of myosin in low ionic strength solution.•His, Imi and Car gave myosin suspensions with small particle size ...species.•His, Imi and Car increased the absolute zeta potential of myosin suspension.•His, Imi and Car induced conformational changes of soluble myosin.•Imidazole ring was the significant constituent in His for solubilising myosin.
Myosin, a major muscle protein, can be solubilised in a low ionic strength solution containing l-histidine (His). To elucidate which chemical constituents in His are responsible for this solubilisation, we investigated the effects of 5mM His, imidazole (Imi), l-α-alanine (Ala), 1-methyl-l-histidine (M-his) and l-carnosine (Car) on particle properties of myosin suspensions and conformational characteristics of soluble myosin at low ionic strength (1mM KCl, pH 7.5). His, Imi and Car, each containing an imidazole ring, were able to induce a myosin suspension, which had small particle size species and high absolute zeta potential, thus increasing the solubility of myosin. His, Imi and Car affected the tertiary structure and decreased the α-helix content of soluble myosin. Therefore, the imidazole ring of His appeared to be the significant chemical constituent in solubilising myosin at low ionic strength solution, presumably by affecting its secondary structure.
Atopic dermatitis (AD) is an incurable, inflammatory skin condition that is prevalent (~20%) in young children. There is an unmet clinical need, particularly in children, for safe interventions that ...target the etiology of the disease. Deficiencies in the skin barrier protein, filaggrin (FLG) have been identified as major predisposing factors in AD. In mammals, ʟ-histidine is rapidly incorporated into epidermal FLG and subsequent FLG proteolysis releases ʟ-histidine as an important natural moisturizing factor (NMF). It has therefore been hypothesized that ʟ-histidine supplementation would be a safe approach to augment both FLG and the NMF, enhance skin barrier function, and reduce AD severity. In a clinical pilot study, adult subjects (n = 24) with AD took either a placebo or 4 g oral ʟ-histidine daily for 8 wk. Unlike the placebo, ʟ-histidine reduced AD (34% reduction in SCORing Atopic Dermatitis scores; P < 0.003) after 4 wk. Nine and 8 adverse events (AEs), and 1 and 0 severe AEs were recorded in the ʟ-histidine or placebo groups, respectively, with no AE being causally related to ʟ-histidine ingestion. A survey of adults (n = 98) taking 4 g ʟ-histidine daily reiterated a lack of causal AEs and also reported a 33% reduction in topical corticosteroid use. A placebo-controlled, clinical pilot study conducted in young children with AD (n = 49; mean age 3.5 y) taking 0.8 g ʟ-histidine daily, showed that eczema area and severity index scores were reduced by 49% (P < 0.02) at 12 wk, whereas a placebo had no effect. The children taking ʟ-histidine had 50 minor AEs (compared with 39 on placebo), with 78% considered as “not,” 18% “unlikely,” and 4% “possibly” related to ʟ-histidine ingestion. These studies indicate that at the levels reported, oral ʟ-histidine supplementation is well tolerated and has potential as a safe intervention for long-term use in the management of AD in all age groups.
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