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<p>Flaviviruses is a genus within the family Flaviviridae. The genus consists of more
than 70 viruses, including important threatening human pathogens such as dengue
virus (DENV), West Nile virus (WNV), and Zika virus (ZIKV). These viruses are
causative agents for a range of mild to lethal diseases and there are currently no US-
licensed therapeutic treatments for infection. The virus genome is a positive-sense,
single-stranded RNA, encoding ten viral proteins. Of the ten flavivirus proteins, Non-
Structural protein 1 (NS1) remains the most elusive in terms of its functions. To date
NS1 has been linked to disease pathology and progression and plays roles in virus
replication and assembly. However, little is understood how NS1 orchestrates these
functions and how NS1 from different viruses function distinctively from one another.
Moreover, flavivirus NS1 has a peculiar ability to associate with lipid membranes.
During the life cycle of NS1, the protein travels through the classical secretory path-
way, similar to infectious virus particles, and is secreted into the extracellular space as
mostly hexameric oligomers containing a lipid core. How the protein binds to lipids
and whether such lipid binding is important for NS1 functions and overall flavivirus
pathology remain unknown. Using structure-based mutagenesis, we found a group
of mutants on WNV NS1, which particularly altered the viral specific infectivity
but maintained wild-type level of virus replication. Purified mutated virus particles
revealed that the specific infectivity alteration was not because of the particle but
interaction of the virus particles and NS1 mutated proteins. Here we demonstrated
that specific residues on NS1 were responsible for distinctly roles in NS1 functions and
the virus specific infectivity was regulated by NS1 protein. In other structure-base study, we focused on the membrane association ability of NS1. All structure-predicted
regions on NS1 were examined for its contribution for the membrane/lipid binding
function. This interaction was required for NS1 biology activities including intracel-
lular trafficking, oligomerization, and endocytosis. The lipidomes from deletion of
each membrane association region revealed differences in lipid classes binding to each
region and the composition flexiblity of the lipid cargo of NS1 hexamer. </p>
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| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/12111486 |
| Date | 17 April 2020 |
| Creators | Thu M Cao (8199633) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/Structure-_Function_Studies_Of_Flavivirus_Non-Structural_Protein1/12111486 |
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