“Histidine kinase”的意思、由来-开放百科全书

In terms of enzymology, a histidine kinase ({{EC number|2.7.13.3}}, EnvZ, histidine protein kinase, protein histidine kinase, protein kinase (histidine), HK1, HP165, Sln1p) is an enzyme that catalyzes the chemical reaction

Thus, the two substrates of this enzyme are ATP and protein L-histidine, whereas its two products are ADP and protein N-phospho-L-histidine.

This type of enzyme is involved in signal transduction pathways upstream of many cellular processes including various metabolic, virulence, and homeostatic pathways.

Mechanism

The mechanism for the reactions catalyzed by histidine kinase have not been completely elucidated, but current evidence suggests that the catalytic domain of one dimeric unit may rotate in such a way that the ATP binding pocket of that unit can come into contact with a particular histidine residue on the opposite unit and a nucleophilic addition results in a phosphorylated histidine.^[7]

Structure and function

An HK is composed of several domains starting with a short N-terminal cytoplasmic portion connected to an extracellular sensing domain via a transmembrane α helix. A second transmembrane α helix connects the extracellular domain to the C-terminal cytoplasmic catalytic domain. HKs are known to serve roles in many different signal transduction pathways, so it is not surprising that the extracellular sensing domain is not very well conserved in the HK family. In contrast, the cytoplasmic domain tends to have high sequence homology and contains several well-known motifs. These motifs include the H, N, G1, F, and G2 boxes.^[8] The autophosphorylation H-box is contained in the N-terminal dimerization and histidine phosphotransfer (DHp) domain. In HK853-CD, crystallized from Thermotoga maritima, this domain is a helical-hairpin and is formed by residues 232-317. The histidine phosphorylation site is located at His-260. The N, G1, F and G2 boxes are contained in the C-terminal catalytic and ATP-binding (CA) domain. This domain is formed by residues 323-489 and forms a structure known as an α/β sandwich fold. This particular fold has one layer composed of a 5-stranded β sheet and the other layer is made of three α helices.

The dimeric unit is held together by a four-helix bundle, formed when the C-terminal segments of the α1 helices on each subunit interact in an antiparallel manner with both α2 helices. The stability of the dimer is aided by several interactions at the interface between the DHps of each monomer. These include hydrophobic interactions between conserved hydrophobic residues as well as two hydrogen bonds (Thr-252^...Glu-316’ and Arg-263^...Asn-307’) and one salt bridge (Lys-270^...Glu-303’). Further interactions are mediated via hydrogen bonds to water within a cavity inside the coiled coil and flanked by hydrophobic residues.

The final side of the ATP binding pocket is conveniently named the “ATP lid.” The stability of this structure is mediated by the presence of the γ phosphate and thus the Mg²⁺ ion in the binding site. Also the presence of the nucleotide base has proved to play a significant role in stabilization of the lid in a closed conformation. The ATP lid is connected via hydrophobic residues to the rest of the protein. The γ phosphate of ATP is somewhat exposed allowing for dephosphorylation.

Upon ATP binding in this pocket, it is believed that a conformational change occurs allowing the rotation of the CA domain to come into contact with the DHp of the other monomer and thus allowing the conserved His-260 to rest near the γ phosphate. The Nε of His-260 then attacks the γ phosphate of ATP in a nucleophilic addition and bumps off ADP as its leaving group.

Role in fungal infections

A two-component system, involving histidine kinase and a variable response regulator protein, may be critical to the virulence of some fungal strains such as Candida albicans, which is often responsible for causing candidiasis in immunocompromised persons.^[10] C. albicans with a deletion of CHK1, the two-component histidine kinase gene, show defects in morphogenesis and a drastic decrease in the cell’s ability to resist elimination by human neutrophils. As humans lack this two-component system, it may be a good target for anti-microbial agents in order to treat candidiasis.

References

1. ^{{cite journal |vauthors=Wolanin PW, Thomason PA, Stock JB |title=Histidine protein kinases: key signal transducers outside the animal kingdom|journal=Genome Biology|volume=3|issue=10|pages=reviews3013.1–3013.8|year=2002|pmid=12372152|pmc=244915|doi=10.1186/gb-2002-3-10-reviews3013}}
2. ^{{cite journal |vauthors=Fuhs SR, Hunter T |title=pHisphorylation: the emergence of histidine phosphorylation as a reversible regulatory modification|journal=Curr Opin Cell Biol|volume=45|pages=8–16|year=2017|pmid=28129587|doi=10.1016/j.ceb.2016.12.010|pmc=5482761}}
3. ^{{cite journal |vauthors=Fuhs SR, Meisenhelder J, Aslanian A, Ma L, Zagorska A, Stankova M, Binnie A, Al-Obeidi F, Mauger J, Lemke G, Yates JR 3rd, Hunter T |title=Monoclonal 1- and 3-Phosphohistidine Antibodies: New Tools to Study Histidine Phosphorylation |journal=Cell|volume=162|issue=1 |pages=198–210|year=2015|pmid=26140597 |doi=10.1016/j.cell.2015.05.046 |pmc=4491144}}
4. ^{{cite journal |vauthors=Gonzalez-Sanchez MB, Lanucara F, Hardman GE, Eyers CE |title=Gas-phase intermolecular phosphate transfer within a phosphohistidine phosphopeptide dimer.|journal=Int J Mass Spectrom|volume=367|pages=28–34|year=2014|pmid=25844054|doi=10.1016/j.ijms.2014.04.015|pmc=4375673}}
5. ^{{cite journal |vauthors=Gonzalez-Sanchez MB, Lanucara F, Helm M, Eyers CE |title=Attempting to rewrite History: challenges with the analysis of histidine-phosphorylated peptides.|journal=Biochem Soc Trans|volume=41|issue=4|pages=1089–1095|year=2013|pmid=23863184|doi=10.1042/bst20130072}}
6. ^{{cite biorxiv |vauthors=Hardman G, Perkins S, Ruan Z, Kannan N, Brownridge P, Byrne DP, Eyers PA, Jones AR, Eyers CE |title= Extensive non-canonical phosphorylation in human cells revealed using strong-anion exchange-mediated phosphoproteomics |date= 13 October 2017 |biorxiv= 202820}}
7. ^¹{{cite journal |vauthors=Marina A, Waldburger CD, Hendrickson WA | title = Structure of the entire cytoplasmic portion of a sensor histidine-kinase protein | journal = EMBO J. | volume = 24 | issue = 24 | pages = 4247–59 |date=December 2005 | pmid = 16319927 | pmc = 1356327 | doi = 10.1038/sj.emboj.7600886 }}
8. ^{{cite journal |vauthors=Parkinson JS, Kofoid EC | title = Communication modules in bacterial signaling proteins | journal = Annu. Rev. Genet. | volume = 26 | issue = | pages = 71–112 | year = 1992 | pmid = 1482126 | doi = 10.1146/annurev.ge.26.120192.000443 }}
9. ^{{cite journal |vauthors=Bilwes AM, Quezada CM, Croal LR, Crane BR, Simon MI | title = Nucleotide binding by the histidine kinase CheA | journal = Nat. Struct. Biol. | volume = 8 | issue = 4 | pages = 353–60 |date=April 2001 | pmid = 11276258 | doi = 10.1038/86243 }}
10. ^{{cite journal |vauthors=Torosantucci A, Chiani P, De Bernardis F, Cassone A, Calera JA, Calderone R | title = Deletion of the Two-Component Histidine Kinase Gene (CHK1) of Candida albicans Contributes to Enhanced Growth Inhibition and Killing by Human Neutrophils In Vitro | journal = Infect. Immun. | volume = 70 | issue = 2 | pages = 985–7 |date=February 2002 | pmid = 11796636 | pmc = 127696 | doi = 10.1128/IAI.70.2.985-987.2002 }}

Mechanism

Structure and function

Role in fungal infections

References

Further reading