Viral Membrane Fusion and the Transmembrane Domain

Barrett, Chelsea T.; Dutch, Rebecca Ellis

doi:10.3390/v12070693

Cited by 47 publications

(50 citation statements)

References 175 publications

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“…Viral fusion proteins are stimulated by a signal during the attachment at the target cell -such as receptor or co-receptor binding or proton binding in an endosome- promoting a series of conformational changes. The hydrophobic segment known as “fusion peptide” triggers the viral-cell membrane fusion, process which requires cooperation between lipids and proteins ( Rawat et al, 2003 ; Harrison, 2015 ; Barrett and Dutch, 2020 ). Viral proteins play an essential role in directing and catalyzing the process, but successful outcome may depend on the lipid composition of both viral and cell membranes.…”

Section: Membrane Rafts In Viral Entry By Fusionmentioning

confidence: 99%

Membrane Rafts: Portals for Viral Entry

et al. 2021

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Membrane rafts are dynamic, small (10–200 nm) domains enriched with cholesterol and sphingolipids that compartmentalize cellular processes. Rafts participate in roles essential to the lifecycle of different viral families including virus entry, assembly and/or budding events. Rafts seem to participate in virus attachment and recruitment to the cell surface, as well as the endocytic and non-endocytic mechanisms some viruses use to enter host cells. In this review, we will introduce the specific role of rafts in viral entry and define cellular factors implied in the choice of one entry pathway over the others. Finally, we will summarize the most relevant information about raft participation in the entry process of enveloped and non-enveloped viruses.

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Section: Membrane Rafts In Viral Entry By Fusionmentioning

confidence: 99%

Membrane Rafts: Portals for Viral Entry

et al. 2021

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“…On the other hand, trimerization is primarily observed for β-barrel proteins on mitochondrial or prokaryotic membranes. Virus fusion proteins are one group where transmembrane helices naturally trimerize (10). Trimeric association of viral transmembrane helices has previously been shown to be important for stability and maturation of the fusion proteins, and mutations that interfere with TM oligomerization alter the structure of the fusion protein (66,67).…”

Section: Discussionmentioning

confidence: 99%

“…CC-BY-NC-ND 4.0 International license made available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.07.447334 doi: bioRxiv preprint and the host lipid bilayers (9,10). Thereafter, the C-terminal HR2 coiled-coil domain, which is closer to the viral envelop, disassembles to refold in an antiparallel manner over the long extended trimer, forming a six-helix bundle often referred to as the fusion core (11).…”

Section: Introductionmentioning

confidence: 99%

“…A large body of evidence backs the important role of the fusion protein transmembrane domain (TMD) in successful completion of viral fusion (10). Classical mutagenesis experiments have established that a sequence-specific, proteinaceous, transmembrane anchor capable of spanning the entire envelope bilayer is a prerequisite for viral entry into cells (12).…”

Section: Introductionmentioning

confidence: 99%

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Sequence of the SARS-CoV-2 spike transmembrane domain makes it inherently dynamic

Lall

Balaram

Gosavi

et al. 2021

Preprint

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The spike (S) protein is a trimeric, membrane-anchored fusion protein that enables coronaviruses, such as the SARS-CoV-2, to recognize and fuse with their hosts' cells. While the prefusion and postfusion structures of the ectomembrane domain of the spike protein are available, the corresponding organization of its transmembrane domain is obscure. Since the transmembrane and ectomembrane domains of fusion proteins are conformationally linked, an understanding of trimerization and transmembrane conformations in the viral envelope is a prerequisite to completely understand viral fusion by the spike protein. To address this, we computationally explored the self-assembly of the SARS-CoV-2 spike transmembrane domain, starting first by determining the membrane boundaries of the spike transmembrane helix. Using atomistic molecular dynamics simulations, we found the spike protein transmembrane domain to be plastic, and the transmembrane helix to be very dynamic. The observed movements of the helix changed the membrane embedded sequence, and thereby affected the conformational ensemble of the transmembrane assembly in Martini coarse grained simulations, even flipping the super-helical handedness. Analysis of the transmembrane organization of the spike transmembrane helix provided rich insights into the interfaces utilized to self-associate. Moreover, we identified two distinct cholesterol binding regions on the transmembrane helix with different affinities for the sterol. The cholesterol binding pockets overlapped with regions involved in the initiation of transmembrane protein-protein interaction. Together, the results from our multiscale simulations not only provide insight into understudied trimeric helical interfaces in biomembranes, but also enhance our understanding of the elusive transmembrane conformational dynamics of SARS-CoV-2 spike and more generally of viral fusion proteins. These insights should enable the inclusion of the conformations of the spike protein transmembrane domain into the prevalent models of virus fusion.

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“…Fusion of membrane enveloped virus particles with host cell membranes is a multi-step process involving membrane merging via a universal “cast-and-fold” mechanism. Fusion-protein-mediated membrane merging is characterized by different intermediate structures including stalk formation, hemifusion, pore formation, pore growth, and, finally, capsid delivery [ 51 , 52 ]. It may be possible that the ability to detect the intermediate state during fusion of FV Env is dependent on the location of the fluorescent tag on the FV glycoprotein.…”

Section: Discussionmentioning

confidence: 99%

Identification of an Intermediate Step in Foamy Virus Fusion

Dupont

Glück

Ponti

et al. 2020

Viruses

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Viral glycoprotein-mediated membrane fusion is an essential step for productive infection of host cells by enveloped viruses; however, due to its rarity and challenges in detection, little is known about the details of fusion events at the single particle level. Here, we have developed dual-color foamy viruses (FVs) composed of eGFP-tagged prototype FV (PFV) Gag and mCherry-tagged Env of either PFV or macaque simian FV (SFVmac) origin that have been optimized for detection of the fusion process. Using our recently developed tracking imaging correlation (TrIC) analysis, we were able to detect the fusion process for both PFV and SFVmac Env containing virions. PFV Env-mediated fusion was observed both at the plasma membrane as well as from endosomes, whereas SFVmac Env-mediated fusion was only observed from endosomes. PFV Env-mediated fusion was observed to happen more often and more rapidly than as for SFVmac Env. Strikingly, using the TrIC method, we detected a novel intermediate state where the envelope and capsids are still tethered but separated by up to 400 nm before final separation of Env and Gag occurred.

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Viral Membrane Fusion and the Transmembrane Domain

Cited by 47 publications

References 175 publications

Membrane Rafts: Portals for Viral Entry

Membrane Rafts: Portals for Viral Entry

Sequence of the SARS-CoV-2 spike transmembrane domain makes it inherently dynamic

Identification of an Intermediate Step in Foamy Virus Fusion

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