![]() ![]() ![]() The interaction between protomers within the dimer is stabilized by a large number of hydrogen bonds 13.Ībout a decade ago, two low-resolution (23 Å and 30 Å) EM structures of sNS1 were determined: a cryoEM structure reconstructed from images acquired by using a negative-stain room temperature EM structure (Supplementary Fig. 1b) 14 and the other, a 120 kV LaB 6-equipped electron microscope (Philip CM12 TEM) 15. One side of the β-ladder faces the hydrophobic β-roll, while the other side is decorated with its highly charged spaghetti loops. The β-ladder domains from the two iNS1 protomers line up with each other to form a long ladder-like pattern. (3) the β-ladder domain (amino acids 182–352), consists of a continuous arrangement of 10 β-strands. The wing domain is the most flexible domain as it differs between different flavivirus NS1 crystal structures 12. (2) Following the β-roll domain is the wing domain (amino acids 31–181). This domain is generally hydrophobic and is thought to interact with cellular membranes. 1a): (1) the N-terminus contains the β-roll domain (amino acids 1–30) that interacts with the same domain from the other protomer within the dimer to form a roll-like structure (named β-roll). Each protomer of the iNS1 contains three domains (Supplementary Fig. There are also crystal structures of the dimeric form of NS1 protein from other flaviviruses 12 and they are largely similar to that of the DENV iNS1. There is a high-resolution crystal structure of full length dimeric dengue iNS1 11 produced by baculovirus expression and subsequent extraction from cellular membrane compartments. Some NS1 is transported to the cell membrane 10, while others are secreted outside the cell, becoming the sNS1. It forms dimers in the ER and then is glycosylated in the trans-Golgi network. INS1 (45 kDa) is first made in the endoplasmic reticulum (ER) as a monomer. sNS1 is therefore an important viral protein both for viral infection (mammalian cells and mosquitoes) and pathogenesis, and it is important to understand the structure of the sNS1 protein. sNS1 was also found to enhance viral infection in mosquitoes by downregulating mosquito midgut immune genes 9. NS1-immune polyclonal serum and anti-NS1 monoclonal antibodies (MAbs) can protect mice against lethal DENV2 challenge 4. Injection of sNS1 alone also causes vascular leakage in mice 4. ![]() Mice injected with sNS1 along with a sublethal dose of DENV were observed to succumb to infection. sNS1 when bound directly to endothelial cells causes barrier dysfunction of the cell monolayer as demonstrated in an in vitro trans-endothelial electrical resistance (TEER) assay 4, 8. sNS1 likely causes vascular leakage symptoms in DHF/DSS via two pathways-indirectly, by stimulating the innate immune response through activation of complement and Toll-like receptors 7, and directly, by binding to endothelial cells causing endothelial hyperpermeability. The extracellular secreted NS1 (sNS1), exists in higher oligomeric forms. ![]() The intracellular NS1 (iNS1), exists as a membrane associated dimeric form and is a part of the viral replication complex. It is a multifunctional protein which exists in different oligomeric forms intracellularly and extracellularly 6, and they play distinctly different roles. NS1 is secreted alongside dengue virus particles during an infection. It has been shown to play an important role in causing the vascular leakage symptoms in DHF/DSS 4, 5. Recently, dengue non-structural protein 1 (NS1) has been investigated as an alternative protein candidate for vaccine development. It has been proven to be difficult to develop an effective vaccine using whole dengue virus or its surface E protein, as the vaccine would need to stimulate equally strong immune responses simultaneously against all four dengue serotypes or else it can lead to a possibility of antibody-dependent enhancement (ADE) of infection 3. Dengvaxia, which is currently the only licensed dengue vaccine, has an overall efficacy of only 45%, and there is a possibility of priming the previously immune naïve children to develop severe disease in subsequent natural infection after vaccination 2. Dengue virus causes disease that ranges from mild dengue fever to the severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) 1. It belongs to the family Flaviviridae, which also includes significant human pathogens, such as West Nile virus (WNV), yellow fever virus (YF) and Zika virus (ZIKV). Dengue is a positive sense single-stranded RNA enveloped virus. ![]()
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