Sandbox Reserved 1102

Function

Zika is a double-stranded RNA virus. The genome replication of double-stranded RNA viruses needs the intervention of a helicase.

Protein from Zika is composed of a protease domain at its N terminus and a helicase domain at its C terminus. The multifunctional helicase belongs to the superfamily 2 (SF2) helicase family. It is this helicase domain that has 5'-triphosphatase activity and that performs the critical and indispensable function of unwinding double-stranded RNA during the step of replication. So it is an essential enzyme involved in the cycles of ATP hydrolysis and behaves as a key molecule in the RNA unwinding. Helicase performs ATP hydrolysis at the 5′ end of RNA to generate energy. During the hydrolysis, the phosphorus atom of the γ-phosphate group of the ATP molecule is cleaved by a water molecule; then, the γ-phosphate group is released with ADP. The break of the this high energy bound from ATP hydrolysis give enough energy to allow move the helicase along nucleic acid strands and unwind the double-stranded RNA genome.

Energy from ATP hydrolysis

This step is among the necessary steps when it comes to viral RNA replication. It creates a favorable environment for polymerization of RNA by an RNA-dependent RNA polymerase and the methylation of RNA by methyltransferase, which is essential for the pathogen development on its host. Moreover, it has been noticed that the viral capacity to replicate may be modified by the ATPase activity and therefore this enzyme would also change the host innate immune response. ^[1]

Structural highlights

The Zika genome is composed of one single-stranded RNA(+). This RNA codes for a polypeptide which is cleaved, during the replication, in 3 structural protein and 7 non-structural protein (including Zika helicase).^[2] 5y6n is a 1 chain protein of 438 residues. There are 2 main activities: ATP binding and helicase activity. Helicase from Zika virus with a specific domain: a serine protease. It is a specific class of protein that hydrolysis peptide bonds from proteins.

The helicase active site has a serine residue that serves as a nucleophilic amino acid. This residue is essential for the catalytic activity of the enzyme. The serine protases present a catalytic triad composed of 3 amino acids His57 Asp102 and Ser195^[3].These 3 amino acids have a specific interaction which is due to the folding of the protein. The tridimentional conformation of the protein brings closer these 3 residues. Their side chains have a specific function:

Serine protease catalysis

Ser195: the hydroxyl group plays the role of a nucleophile that attacks the substrate.

His57: the nitrogen receives an hydrogen from the hydroxyl group of Ser195.

Asp102: this amino acid allows to increase the electronegativity of His157 nitrogen by making hydrogen bond with His157.

All these reactions allow to cleave the substrate by attacking its carbonyl group.

There are two ligands for zika helicase : ADP and Manganese II ion

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There is a strong interrelationship between both ligands. The interactions between Zika helicase and these ligands are still studied to better understand their function and develop therapy.

Disease

Zika virus (ZIKV) ^[4] is a member of the Flavivirus genus, of the virus family Flaviviridae. The Flavivirus genus comprises the dengue virus (DENV), yellow fever virus, West Nile virus, Japanese encephalitis virus, and tick-borne encephalitis virus. It is transmitted by daytime-active Aedes mosquitoes, it can also be sexually transmitted, by blood transfusion or from mother to child.

The incubation period (the time from exposure to symptoms) of Zika virus disease is estimated to be 3–14 days.

Only one over five infected people shows mild symptoms like skin rash, fever ("Zika fever"), joint pain, conjunctivitis and less often muscle pain, headache and vomiting. After a few days, the symptoms subside.

An increased risk of neurologic complications is associated with Zika virus infection in adults and children, including Guillain-Barré syndrome, neuropathy and myelitis. Infection during first trimester of pregnancy can cause microcephaly in newborn children. ^[5]

Like all viruses, Zika virus needs to express itself in its host. The helicase permits the unwinding of the DNA, and finally the virus replication.

It is the non-structural protein 3 (NS3) of the helicase, that is involved in ATP hydrolysis, RNA unwinding and that provides the conditions for RNA polymerization and methylation of RNA which ZIKV needs for replication.

Relevance

There are still no vaccines against Zika virus but the study of zika helicase is one of the most promising area for scientific research. It is an enzyme essential for the virulence of Zika virus and blocking its activity may be a means to struggle against this virus. The development of inhibitors targeting the viral helicase is becoming more and more studied by researchers. ^[6]

References

1. ↑ Xu S, Ci Y, Wang, Yang, Zhang L, Xu C, Qin C, Shi L. Zika virus NS3 is a canonical RNA helicase stimulated by NS5 RNA polymerase.Nucleic Acids Res. 2019 Sep 19;47(16):8693-8707. doi: 10.1093/nar/gkz650.https://www.ncbi.nlm.nih.gov/pubmed/31361901
2. ↑ Hongliang Tian, Xiaoyun Ji, Xiaoyun Yang, Zhongxin Zhang, Zuokun Lu, Kailin Yang, Cheng Chen, Qi Zhao, Heng Chi, Zhongyu Mu, Wei Xie, Zefang Wang, Huiqiang Lou, Haitao Yang and Zihe Rao. Structural basis of Zika virus helicase in recognizing its substrates[J]. Protein&Cell, 2016, 7(8): 562-570. doi: 10.1007/s13238-016-0293-2 http://www.protein-cell.org/en/article/doi/10.1007/s13238-016-0293-2
3. ↑ Enrico Di Cera, Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Box 8231, St. Louis, MO, USA; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2675663/
4. ↑ , "Xiaoyun Yang, Cheng Chen, Hongliang Tian, Heng Chi, Zhongyu Mu, Tianqing Zhang, Kailin Yang, Qi Zhao, Xiaohua Liu, Zefang Wang, Xiaoyun Ji, and Haitao Yang, Mechanism of ATP hydrolysis by the Zika virus helicase, FASEBjournal, pp 5250-5257„ https://www.ncbi.nlm.nih.gov/pubmed/29913559
5. ↑ , " Zhexing Wen, Hongjun Songand, Guo-li Ming, How does Zika virus cause microcephaly?, Genes & Dev, 2017 " doi: 10.1101/gad.298216.117
6. ↑ Ana Paula Valente, Adolfo Henrique Moraes. The Journal of Venomous Animals and Toxins Including Tropical Diseases Zika virus proteins at an atomic scale: how does structural biology help us to understand and develop vaccines and drugs against Zika virus infection? https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727858/