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Structural insight and flexible features of NS5 proteins from all four serotypes of Dengue virus in solution.

ABSTRACT: Infection by the four serotypes of Dengue virus (DENV-1 to DENV-4) causes an important arthropod-borne viral disease in humans. The multifunctional DENV nonstructural protein 5 (NS5) is essential for capping and replication of the viral RNA and harbours a methyltransferase (MTase) domain and an RNA-dependent RNA polymerase (RdRp) domain. In this study, insights into the overall structure and flexibility of the entire NS5 of all four Dengue virus serotypes in solution are presented for the first time. The solution models derived revealed an arrangement of the full-length NS5 (NS5FL) proteins with the MTase domain positioned at the top of the RdRP domain. The DENV-1 to DENV-4 NS5 forms are elongated and flexible in solution, with DENV-4 NS5 being more compact relative to NS5 from DENV-1, DENV-2 and DENV-3. Solution studies of the individual MTase and RdRp domains show the compactness of the RdRp domain as well as the contribution of the MTase domain and the ten-residue linker region to the flexibility of the entire NS5. Swapping the ten-residue linker between DENV-4 NS5FL and DENV-3 NS5FL demonstrated its importance in MTase-RdRp communication and in concerted interaction with viral and host proteins, as probed by amide hydrogen/deuterium mass spectrometry. Conformational alterations owing to RNA binding are presented.

SUBMITTER: Saw WG

PROVIDER: S-EPMC4631481 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Structural insight and flexible features of NS5 proteins from all four serotypes of Dengue virus in solution.

Saw Wuan Geok WG Tria Giancarlo G Grüber Ardina A Subramanian Manimekalai Malathy Sony MS Zhao Yongqian Y Chandramohan Arun A Srinivasan Anand Ganesh G Matsui Tsutomu T Weiss Thomas M TM Vasudevan Subhash G SG Grüber Gerhard G

Acta crystallographica. Section D, Biological crystallography 20151031 Pt 11

Infection by the four serotypes of Dengue virus (DENV-1 to DENV-4) causes an important arthropod-borne viral disease in humans. The multifunctional DENV nonstructural protein 5 (NS5) is essential for capping and replication of the viral RNA and harbours a methyltransferase (MTase) domain and an RNA-dependent RNA polymerase (RdRp) domain. In this study, insights into the overall structure and flexibility of the entire NS5 of all four Dengue virus serotypes in solution are presented for the first ...[more]

PMID: 26527147

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Project description:Any potential dengue virus (DENV) vaccine needs to elicit protective immunity against strains from all four serotypes to avoid potential antibody-dependent enhancement (ADE). In this study, four independent DENV envelope (E) glycoproteins were generated using wild-type E sequences from viruses isolated between 1943 and 2006 using computationally optimized broadly reactive antigen (COBRA) methodology. COBRA and wild-type E antigens were expressed on the surface of subvirion viral particles (SVPs). Four separate wild-type E antigens were used for each serotype. Mice vaccinated with wild-type DENV SVPs had anti-E IgG antibodies that neutralized serotype-specific viruses. COBRA DENV SVPs elicited a broader breadth of antibodies that neutralized strains across all four serotypes. Two COBRA DENV vaccine candidates that elicited the broadest breadth of neutralizing antibodies in mice were used to vaccinate rhesus macaques (Macaca mulatta) that either were immunologically naive to any DENV serotype or had preexisting antibodies to DENV. Antibodies elicited by COBRA DENV E immunogens neutralized all 12 strains of DENV in vitro, which was comparable to antibodies elicited by a tetravalent wild-type E SVP vaccination mixture. Therefore, using a single DENV COBRA E protein can elicit neutralizing antibodies against strains representing all four serotypes of DENV in both naive and dengue virus-preimmune populations.IMPORTANCE Dengue virus infects millions of people living in tropical areas of the world. Dengue virus-induced diseases can range from mild to severe with death. An effective vaccine will need to neutralize viruses from all four serotypes of dengue virus without inducing enhanced disease. A dengue virus E vaccine candidate generated by computationally optimized broadly reactive antigen algorithms elicits broadly neutralizing protection for currently circulating strains from all four serotypes regardless of immune status. Most dengue vaccines in development formulate four separate components based on prM-E from a wild-type strain representing each serotype. Designing a monovalent vaccine that elicits protective immunity against all four serotypes is an effective and economical strategy.

Dataset Information

Structural insight and flexible features of NS5 proteins from all four serotypes of Dengue virus in solution.

Publications

Structural insight and flexible features of NS5 proteins from all four serotypes of Dengue virus in solution.

Similar Datasets

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