6wxe
Cryo-EM reconstruction of VP5*/VP8* assembly from rhesus rotavirus particles - Upright conformation
Structural highlights
FunctionG0YZG6_ROTRH Outer capsid protein VP4: Spike-forming protein that mediates virion attachment to the host epithelial cell receptors and plays a major role in cell penetration, determination of host range restriction and virulence. Rotavirus attachment and entry into the host cell probably involves multiple sequential contacts between the outer capsid proteins VP4 and VP7, and the cell receptors. It is subsequently lost, together with VP7, following virus entry into the host cell. Following entry into the host cell, low intracellular or intravesicular Ca(2+) concentration probably causes the calcium-stabilized VP7 trimers to dissociate from the virion. This step is probably necessary for the membrane-disrupting entry step and the release of VP4, which is locked onto the virion by VP7. During the virus exit from the host cell, VP4 seems to be required to target the newly formed virions to the host cell lipid rafts.[HAMAP-Rule:MF_04132] Outer capsid protein VP5*: Forms the spike 'foot' and 'body' and acts as a membrane permeabilization protein that mediates release of viral particles from endosomal compartments into the cytoplasm. During entry, the part of VP5* that protrudes from the virus folds back on itself and reorganizes from a local dimer to a trimer. This reorganization may be linked to membrane penetration by exposing VP5* hydrophobic region. In integrin-dependent strains, VP5* targets the integrin heterodimer ITGA2/ITGB1 for cell attachment.[HAMAP-Rule:MF_04132] Outer capsid protein VP8*: Forms the head of the spikes and mediates the recognition of specific host cell surface glycans. It is the viral hemagglutinin and an important target of neutralizing antibodies. In sialic acid-dependent strains, VP8* binds to host cell sialic acid, most probably a ganglioside, providing the initial contact. In some other strains, VP8* mediates the attachment to histo-blood group antigens (HBGAs) for viral entry.[HAMAP-Rule:MF_04132] Publication Abstract from PubMedA non-enveloped virus requires a membrane lesion to deliver its genome into a target cell(1). For rotaviruses, membrane perforation is a principal function of the viral outer-layer protein, VP4(2,3). Here we describe the use of electron cryomicroscopy to determine how VP4 performs this function and show that when activated by cleavage to VP8* and VP5*, VP4 can rearrange on the virion surface from an 'upright' to a 'reversed' conformation. The reversed structure projects a previously buried 'foot' domain outwards into the membrane of the host cell to which the virion has attached. Electron cryotomograms of virus particles entering cells are consistent with this picture. Using a disulfide mutant of VP4, we have also stabilized a probable intermediate in the transition between the two conformations. Our results define molecular mechanisms for the first steps of the penetration of rotaviruses into the membranes of target cells and suggest similarities with mechanisms postulated for other viruses. Functional refolding of the penetration protein on a non-enveloped virus.,Herrmann T, Torres R, Salgado EN, Berciu C, Stoddard D, Nicastro D, Jenni S, Harrison SC Nature. 2021 Feb;590(7847):666-670. doi: 10.1038/s41586-020-03124-4. Epub 2021 , Jan 13. PMID:33442061[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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