View source for 8ys4


==Overall structure of Eastern Equine Encephalitis virus VLP in complex with the receptor VLDLR LA3-5==
<StructureSection load='8ys4' size='340' side='right'caption='[[8ys4]], [[Resolution|resolution]] 4.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8ys4]] is a 20 chain structure with sequence from [https://en.wikipedia.org/wiki/Eastern_equine_encephalitis_virus Eastern equine encephalitis virus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8YS4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8YS4 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.8&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8ys4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ys4 OCA], [https://pdbe.org/8ys4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ys4 RCSB], [https://www.ebi.ac.uk/pdbsum/8ys4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ys4 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/POLS_EEEVF POLS_EEEVF] Forms an icosahedral capsid with a T=4 symmetry composed of 240 copies of the capsid protein surrounded by a lipid membrane through which penetrate 80 spikes composed of trimers of E1-E2 heterodimers (By similarity). The capsid protein binds to the viral RNA genome at a site adjacent to a ribosome binding site for viral genome translation following genome release (By similarity). Possesses a protease activity that results in its autocatalytic cleavage from the nascent structural protein (By similarity). 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 icosahedric core particles (By similarity). The resulting nucleocapsid eventually associates with the cytoplasmic domain of the spike glycoprotein E2 at the cell membrane, leading to budding and formation of mature virions (By similarity). In case of infection, new virions attach to target cells and after clathrin-mediated endocytosis their membrane fuses with the host endosomal membrane (By similarity). This leads to the release of the nucleocapsid into the cytoplasm, followed by an uncoating event necessary for the genomic RNA to become accessible (By similarity). The uncoating might be triggered by the interaction of capsid proteins with ribosomes (By similarity). Binding of ribosomes would release the genomic RNA since the same region is genomic RNA-binding and ribosome-binding (By similarity). Specifically inhibits interleukin-1 receptor-associated kinase 1/IRAK1-dependent signaling during viral entry, representing a means by which the alphaviruses may evade innate immune detection and activation prior to viral gene expression (By similarity). Inhibits host transcription (By similarity). Forms a tetrameric complex with XPO1/CRM1 and the nuclear import receptor importin (By similarity). This complex blocks the central channel of host nuclear pores thereby inhibiting the receptor-mediated nuclear transport and thus the host mRNA and rRNA transcription (By similarity). The inhibition of transcription is linked to a cytopathic effect on the host cell (By similarity).[UniProtKB:P03315][UniProtKB:P03316][UniProtKB:P09592][UniProtKB:P27284][UniProtKB:P36329]  Provides the signal sequence for the translocation of the precursor of protein E3/E2 to the host endoplasmic reticulum. Furin-cleaved E3 remains associated with spike glycoprotein E1 and mediates pH protection of the latter during the transport via the secretory pathway. After virion release from the host cell, the assembly protein E3 is gradually released in the extracellular space.[UniProtKB:P03315]  Plays a role in 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.[UniProtKB:P03315]  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.[UniProtKB:P03315]  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. Fusion is optimal at levels of about 1 molecule of cholesterol per 2 molecules of phospholipids, and is specific for sterols containing a 3-beta-hydroxyl group.[UniProtKB:P03315]
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== Publication Abstract from PubMed ==
Eastern Equine Encephalitis virus (EEEV) is an alphavirus that can cause severe diseases in infected humans. The very low-density lipoprotein receptor (VLDLR) was recently identified as a receptor of EEEV. Herein, we performed cryo-electron microscopy structural and biochemistry studies on the specific interactions between EEEV and VLDLR. Our results show that VLDLR binds EEEV at three different sites A, B and C through its membrane-distal LDLR class A (LA) repeats. Site A is located in the cleft in between the E1-E2 heterodimers. Site B is located near the connecting beta ribbon of E2 and is in proximity to site A, while site C is on the domain B of E2. The binding of VLDLR LAs to EEEV is in complex modes, including the LA1-2 and LA3-5 mediated two major modes. Disruption of the LA1-2 mediated binding significantly affect the cell attachment of EEEV. However, the mutation W132G of VLDLR impairs the binding of LA3, drives the switch of the binding modes, and significantly enhances the attachment of EEEV to the cell. The W132G variant of VLDLR could be identified in human genome and SNP sequences, implying that people with similar mutations in VLDLR may be highly susceptible to EEEV infection.

The receptor VLDLR binds Eastern Equine Encephalitis virus through multiple distinct modes.,Cao D, Ma B, Cao Z, Xu X, Zhang X, Xiang Y Nat Commun. 2024 Aug 10;15(1):6866. doi: 10.1038/s41467-024-51293-x. PMID:39127734<ref>PMID:39127734</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8ys4" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Eastern equine encephalitis virus]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cao D]]
[[Category: Cao Z]]
[[Category: Ma B]]
[[Category: Xiang Y]]
[[Category: Xu X]]
[[Category: Zhang X]]