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Basic information and current topics regarding Flaviviridae
The flavivirus envelope (E) protein is a capsid protein that is critical for attachment and entry into the host cell, viral-endosome membrane fusion, and assembly of the newly made virus progeny. A recent study set out to determine what kind of changes in amino acids that make up the E protein hinge region could affect the ability for the type 2 Dengue Virus to infection and fuse with the endosome1. Previous crystallography studies indicated that the E protein consists of 3 domains; DI, DII, and DIII. The hinge region (H region) is made up of four peptide strands (H1-H4) that connect DI and DIII. This region functions in fusing the virus to the endosome during low pH-induced reorganization of the E protein. During low pH conditions the H region functions to allow flexibility that is needed for the conformational changes that occur in the E protein 1. Determining these changes in the E protein may help to give scientists insight into potential targets in regards to antivirals. Furthermore, if we know what changes occur in this protein during infection, we may be able to target this and possibly block the changes from occurring, essentially making the virus incapable of infection!
Butrapet, S. et al conducted a 2011 study in which they engineered 15 mutant dengue viruses (mutations all within the four hinge proteins) in order to identify the amino acids located in the molecular hinge areas of the E protein that are required for proper viral infection. Overall, the study indicated a total of nine mutations that influenced the infectivity rate of DENV2 in both mosquito and mammalian cells, as well as in A. aegypti mosquitoes. Of all the mutants, the L135G mutation seemed to change the infectivity of this virus (compared to wild type) most significantly, leading to a virus that was not viable at 37°C (human body temperature)! This mutation also reduced the viruses’ ability to fuse or mature properly. The authors also concluded the following affects of mutations at specific amino acids:
– Reduced infectivity (mammalian cells) and a change in the viruses’ ability to fuse at a pH between 6.0-6.8 occurred in mutations at Q52, A54 and E133.
– Viral replication rate was decreased in mammalian and mosquito cells when mutations were present at F193, I270, G281, and G266.
This paper is interesting in terms of increasing our knowledge of the flavivirus and how the sequence of it’s amino acids play a large role in the proper functioning of infectivity! Below is the link to the journal article. Enjoy!
Butrapet, S., Childers, T., et al. (2011). Amino acid changes within the E protein hinge region that affect dengue virus type 2 infectivity and fusion. Virology. 413: 118-127