| Structural highlights
Function
[POLS_SINDV] Capsid protein possesses a protease activity that results in its autocatalytic cleavage from the nascent structural protein. Following its self-cleavage, the capsid protein transiently associates with ribosomes, and within several minutes the protein binds to viral RNA and rapidly assembles into icosaedric core particles. The resulting nucleocapsid eventually associates with the cytoplasmic domain of E2 at the cell membrane, leading to budding and formation of mature virions. New virions attach to target cells, and after clathrin-mediated endocytosis their membrane fuses with the host endosomal membrane. This leads to the release of the nucleocapsid into the cytoplasm, followed by an uncoating event necessary for the genomic RNA to become accessible. The uncoating might be triggered by the interaction of capsid proteins with ribosomes. Binding of ribosomes would release the genomic RNA since the same region is genomic RNA-binding and ribosome-binding (By similarity).[1] [2] [3] [4] E3 protein's function is unknown (By similarity).[5] [6] [7] [8] E2 is responsible for viral attachment to target host cell, by binding to the cell receptor. Synthesized as a p62 precursor which is processed by furin at the cell membrane just before virion budding, giving rise to E2-E1 heterodimer. The p62-E1 heterodimer is stable, whereas E2-E1 is unstable and dissociate at low pH. p62 is processed at the last step, presumably to avoid E1 fusion activation before its final export to cell surface. E2 C-terminus contains a transitory transmembrane that would be disrupted by palmitoylation, resulting in reorientation of the C-terminal tail from lumenal to cytoplasmic side. This step is critical since E2 C-terminus is involved in budding by interacting with capsid proteins. This release of E2 C-terminus in cytoplasm occurs lately in protein export, and precludes premature assembly of particles at the endoplasmic reticulum membrane (By similarity).[9] [10] [11] [12] 6K is a constitutive membrane protein involved in virus glycoprotein processing, cell permeabilization, and the budding of viral particles. Disrupts the calcium homeostasis of the cell, probably at the endoplasmic reticulum level. This leads to cytoplasmic calcium elevation. Because of its lipophilic properties, the 6K protein is postulated to influence the selection of lipids that interact with the transmembrane domains of the glycoproteins, which, in turn, affects the deformability of the bilayer required for the extreme curvature that occurs as budding proceeds. Present in low amount in virions, about 3% compared to viral glycoproteins.[13] [14] [15] [16] E1 is a class II viral fusion protein. Fusion activity is inactive as long as E1 is bound to E2 in mature virion. After virus attachment to target cell and endocytosis, acidification of the endosome would induce dissociation of E1/E2 heterodimer and concomitant trimerization of the E1 subunits. This E1 trimer is fusion active, and promotes release of viral nucleocapsid in cytoplasm after endosome and viral membrane fusion. Efficient fusion requires the presence of cholesterol and sphingolipid in the target membrane (By similarity).[17] [18] [19] [20]
Publication Abstract from PubMed
Alphaviruses are enveloped RNA viruses that have a diameter of about 700 A and can be lethal human pathogens. Entry of virus into host cells by endocytosis is controlled by two envelope glycoproteins, E1 and E2. The E2-E1 heterodimers form 80 trimeric spikes on the icosahedral virus surface, 60 with quasi-three-fold symmetry and 20 coincident with the icosahedral three-fold axes arranged with T = 4 quasi-symmetry. The E1 glycoprotein has a hydrophobic fusion loop at one end and is responsible for membrane fusion. The E2 protein is responsible for receptor binding and protects the fusion loop at neutral pH. The lower pH in the endosome induces the virions to undergo an irreversible conformational change in which E2 and E1 dissociate and E1 forms homotrimers, triggering fusion of the viral membrane with the endosomal membrane and then releasing the viral genome into the cytoplasm. Here we report the structure of an alphavirus spike, crystallized at low pH, representing an intermediate in the fusion process and clarifying the maturation process. The trimer of E2-E1 in the crystal structure is similar to the spikes in the neutral pH virus except that the E2 middle region is disordered, exposing the fusion loop. The amino- and carboxy-terminal domains of E2 each form immunoglobulin-like folds, consistent with the receptor attachment properties of E2.
Structural changes of envelope proteins during alphavirus fusion.,Li L, Jose J, Xiang Y, Kuhn RJ, Rossmann MG Nature. 2010 Dec 2;468(7324):705-8. PMID:21124457[21]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Smit JM, Bittman R, Wilschut J. Low-pH-dependent fusion of Sindbis virus with receptor-free cholesterol- and sphingolipid-containing liposomes. J Virol. 1999 Oct;73(10):8476-84. PMID:10482600
- ↑ DeTulleo L, Kirchhausen T. The clathrin endocytic pathway in viral infection. EMBO J. 1998 Aug 17;17(16):4585-93. PMID:9707418 doi:10.1093/emboj/17.16.4585
- ↑ Sanz MA, Madan V, Carrasco L, Nieva JL. Interfacial domains in Sindbis virus 6K protein. Detection and functional characterization. J Biol Chem. 2003 Jan 17;278(3):2051-7. Epub 2002 Nov 6. PMID:12424249 doi:10.1074/jbc.M206611200
- ↑ Antoine AF, Montpellier C, Cailliau K, Browaeys-Poly E, Vilain JP, Dubuisson J. The alphavirus 6K protein activates endogenous ionic conductances when expressed in Xenopus oocytes. J Membr Biol. 2007 Jan;215(1):37-48. Epub 2007 May 5. PMID:17483865 doi:10.1007/s00232-007-9003-6
- ↑ Smit JM, Bittman R, Wilschut J. Low-pH-dependent fusion of Sindbis virus with receptor-free cholesterol- and sphingolipid-containing liposomes. J Virol. 1999 Oct;73(10):8476-84. PMID:10482600
- ↑ DeTulleo L, Kirchhausen T. The clathrin endocytic pathway in viral infection. EMBO J. 1998 Aug 17;17(16):4585-93. PMID:9707418 doi:10.1093/emboj/17.16.4585
- ↑ Sanz MA, Madan V, Carrasco L, Nieva JL. Interfacial domains in Sindbis virus 6K protein. Detection and functional characterization. J Biol Chem. 2003 Jan 17;278(3):2051-7. Epub 2002 Nov 6. PMID:12424249 doi:10.1074/jbc.M206611200
- ↑ Antoine AF, Montpellier C, Cailliau K, Browaeys-Poly E, Vilain JP, Dubuisson J. The alphavirus 6K protein activates endogenous ionic conductances when expressed in Xenopus oocytes. J Membr Biol. 2007 Jan;215(1):37-48. Epub 2007 May 5. PMID:17483865 doi:10.1007/s00232-007-9003-6
- ↑ Smit JM, Bittman R, Wilschut J. Low-pH-dependent fusion of Sindbis virus with receptor-free cholesterol- and sphingolipid-containing liposomes. J Virol. 1999 Oct;73(10):8476-84. PMID:10482600
- ↑ DeTulleo L, Kirchhausen T. The clathrin endocytic pathway in viral infection. EMBO J. 1998 Aug 17;17(16):4585-93. PMID:9707418 doi:10.1093/emboj/17.16.4585
- ↑ Sanz MA, Madan V, Carrasco L, Nieva JL. Interfacial domains in Sindbis virus 6K protein. Detection and functional characterization. J Biol Chem. 2003 Jan 17;278(3):2051-7. Epub 2002 Nov 6. PMID:12424249 doi:10.1074/jbc.M206611200
- ↑ Antoine AF, Montpellier C, Cailliau K, Browaeys-Poly E, Vilain JP, Dubuisson J. The alphavirus 6K protein activates endogenous ionic conductances when expressed in Xenopus oocytes. J Membr Biol. 2007 Jan;215(1):37-48. Epub 2007 May 5. PMID:17483865 doi:10.1007/s00232-007-9003-6
- ↑ Smit JM, Bittman R, Wilschut J. Low-pH-dependent fusion of Sindbis virus with receptor-free cholesterol- and sphingolipid-containing liposomes. J Virol. 1999 Oct;73(10):8476-84. PMID:10482600
- ↑ DeTulleo L, Kirchhausen T. The clathrin endocytic pathway in viral infection. EMBO J. 1998 Aug 17;17(16):4585-93. PMID:9707418 doi:10.1093/emboj/17.16.4585
- ↑ Sanz MA, Madan V, Carrasco L, Nieva JL. Interfacial domains in Sindbis virus 6K protein. Detection and functional characterization. J Biol Chem. 2003 Jan 17;278(3):2051-7. Epub 2002 Nov 6. PMID:12424249 doi:10.1074/jbc.M206611200
- ↑ Antoine AF, Montpellier C, Cailliau K, Browaeys-Poly E, Vilain JP, Dubuisson J. The alphavirus 6K protein activates endogenous ionic conductances when expressed in Xenopus oocytes. J Membr Biol. 2007 Jan;215(1):37-48. Epub 2007 May 5. PMID:17483865 doi:10.1007/s00232-007-9003-6
- ↑ Smit JM, Bittman R, Wilschut J. Low-pH-dependent fusion of Sindbis virus with receptor-free cholesterol- and sphingolipid-containing liposomes. J Virol. 1999 Oct;73(10):8476-84. PMID:10482600
- ↑ DeTulleo L, Kirchhausen T. The clathrin endocytic pathway in viral infection. EMBO J. 1998 Aug 17;17(16):4585-93. PMID:9707418 doi:10.1093/emboj/17.16.4585
- ↑ Sanz MA, Madan V, Carrasco L, Nieva JL. Interfacial domains in Sindbis virus 6K protein. Detection and functional characterization. J Biol Chem. 2003 Jan 17;278(3):2051-7. Epub 2002 Nov 6. PMID:12424249 doi:10.1074/jbc.M206611200
- ↑ Antoine AF, Montpellier C, Cailliau K, Browaeys-Poly E, Vilain JP, Dubuisson J. The alphavirus 6K protein activates endogenous ionic conductances when expressed in Xenopus oocytes. J Membr Biol. 2007 Jan;215(1):37-48. Epub 2007 May 5. PMID:17483865 doi:10.1007/s00232-007-9003-6
- ↑ Li L, Jose J, Xiang Y, Kuhn RJ, Rossmann MG. Structural changes of envelope proteins during alphavirus fusion. Nature. 2010 Dec 2;468(7324):705-8. PMID:21124457 doi:10.1038/nature09546
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