Cryo-EM structures reveal the molecular basis of receptor-initiated coxsackievirus uncoating

Molecular basis of differential receptor usage for naturally occurring CD55-binding and -nonbinding coxsackievirus B3 strains

“…We observed that neutral pH could induce pocket factor release of CVB3 virions after binding to CAR, which is consistent with data from Xu et al. showing that CAR binding to the CVB1 virion canyon leads to viral uncoating under neutral pH ( 26 ). Hence, it is reasonable to suggest that the mature virus particles may transform into A particles on the cell membrane and provide an alternative pathway to entry into cells.…”

“…However, for the same incubation time, CVB3E already started its uncoating process, with the pocket factor being released from the capsid along with a slight downshift of the VP1 GH loop (residues 208 to 216) ( Fig. 4 I and J ), which is regarded as the gating loop responsible for receptor binding and pocket factor ejection in many enterovirus virions ( 11 , 26 ). These results indicate that the binding of CAR, but not CD55, to CVB3 full virions can initiate viral uncoating, with slightly different efficiencies among CVB3 strains.…”

“…An acidic environment could trigger more significant conformational changes in the VP1 GH loop of some enterovirus virions ( 11 , 12 ). This has been proposed as a sensor loop that can initiate a cascade of events, including the release of the pocket factor and the formation of A particles and empty particles ( 26 ). Additionally, temperature can affect the uncoating efficiency observed in some enteroviruses ( 13 ), indicating that the trigger mechanism for virus uncoating may be diverse.…”

“…For most enteroviruses, including EV71 ( 24 ), CVA10 ( 12 ), and Echo 6 ( 11 ), both receptor binding and exposure to low pH in the endosomal system could cause pocket factor extrusion, followed by the formation of an expanded uncoating intermediate (A particle) by the opening of a channel near the icosahedral twofold axis and subsequent genome release. Recent findings indicate that receptor binding under neutral pH for some enteroviruses can also trigger viral uncoating ( 16 , 25 , 26 ). As the cell-adhesion molecule found in tight junctions, CAR has been previously identified as a universal uncoating receptor for CVB and plays a crucial role in CVB-related pathology ( 27 ).…”

Imaging Flow Cytometry and Confocal Immunofluorescence Microscopy of Virus-Host Cell Interactions

“…Similarly, in cryo-EM studies of the RNA polymerase of influenza A virus, potential target sites identified for the development of antivirals include polymerase dimerization sites and cRNA promoter-binding sites ( Fan et al., 2019 ). Discoveries such as these based on cryo-EM imaging have been used to inform potential new vaccines and antibody designs against other viruses, including HIV, group B coxsackieviruses, and SARS-CoV-2 ( Lee et al., 2016 ; Wang et al., 2021 ; Xu et al., 2021 ). Recently, structural information gathered via cryo-EM has characterized helicase-promoted backtracking activity by the RNA polymerase of SARS-CoV-2 ( Malone et al., 2021 ).…”