2m0s | pdb_00002m0s
Solution Structure of the trans-membrane domain of the NS2A of dengue virus
Structural highlights
FunctionQ9YKL3_9FLAV Envelope protein E binding to host cell surface receptor is followed by virus internalization through clathrin-mediated endocytosis. Envelope protein E is subsequently involved in membrane fusion between virion and host late endosomes. Synthesized as a homodimer with prM which acts as a chaperone for envelope protein E. After cleavage of prM, envelope protein E dissociate from small envelope protein M and homodimerizes (By similarity).[SAAS:SAAS013754_004_099774] Publication Abstract from PubMedFlavivirus non-structural protein 2A (NS2A) is a component of viral replication complex, functions in virion assembly, and antagonizes host immune response. Although flavivirus NS2A is known to associate with endoplasmic reticulum (ER) membrane, the detailed topology of this protein has not been determined. Here we report the first topology model of flavivirus NS2A on ER membrane. Using dengue virus (DENV) NS2A as a model, we show that (i) the N-terminal 68 amino acids are located in ER lumen with one segment (amino acids 30-52) that interacts with ER membrane without traversing the lipid bilayer; (ii) amino acids 69 to 209 form five trans-membrane segments, each of which integrally spans the ER membrane; (iii) the C-terminal tail (amino acids 210-218) is located in cytosol. NMR structural analysis showed that the first membrane-spanning segment (amino acids 69-93) consists of two helices separated by a helix "breaker". The helix "breaker" is formed by amino acid P85 and one positively charged residue R84. Functional analysis using replicon and genome-length RNAs of DENV-2 indicates that P85 is not important for viral replication. However, when R84 was substituted with E, the R84E mutation attenuated both viral RNA synthesis and virus production. Remarkably, when R84 was changed to A, the R84A mutation did not affect viral RNA synthesis, but blocked intracellular formation of infectious virions. Collectively, the mutagenesis results demonstrate that NS2A functions in both DENV RNA synthesis and virion assembly/maturation. The topology model of DENV NS2A provides a good starting point to study how flavivirus NS2A modulates viral replication and evasion of host immune response. Membrane topology and function of dengue virus NS2A protein.,Xie X, Gayen S, Kang C, Yuan Z, Shi PY J Virol. 2013 Feb 13. PMID:23408612[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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