Functional analysis of the cytoplasmic tail of Moloney murine leukemia virus envelope protein

Januszeski, Michael M.; Cannon, Paula M.; Chen, D; Rozenberg, Yanina Y.; Anderson, W. French

doi:10.1128/jvi.71.5.3613-3619.1997

Cited by 90 publications

(43 citation statements)

References 42 publications

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“…The arrowheads in E and F point to cells from the control sample that are stained with fluorescein but not R18. all or part of the cytoplasmic tail enhances membrane fusion, as demonstrated for simian immunodeficiency virus (Ritter et al, 1993), HIV (Dubay et al, 1992;Wilk et al, 1992), Mason-Pfizer monkey virus (Brody et al, 1994), and murine leukemia virus (Januszeski et al, 1997;Ragheb and Anderson, 1994a;Compans, 1996, 1997). In the last case, deletion of the C-terminal 16 amino acids of the env glycoprotein removes the R peptide, which is responsible for the inhibition of fusogenic activity (Ragheb and Anderson, 1994a;Rein et al, 1994;Yang and Compans, 1996).…”

Section: Discussionmentioning

confidence: 89%

Coronavirus-Induced Membrane Fusion Requires the Cysteine-Rich Domain in the Spike Protein

2000

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The spike glycoprotein of mouse hepatitis virus strain A59 mediates the early events leading to infection of cells, including fusion of the viral and cellular membranes. The spike is a type I membrane glycoprotein that possesses a conserved transmembrane anchor and an unusual cysteine-rich (cys) domain that bridges the putative junction of the anchor and the cytoplasmic tail. In this study, we examined the role of these carboxyl-terminal domains in spike-mediated membrane fusion. We show that the cytoplasmic tail is not required for fusion but has the capacity to enhance membrane fusion activity. Chimeric spike protein mutants containing substitutions of the entire transmembrane anchor and cys domain with the herpes simplex virus type 1 glycoprotein D (gD-1) anchor demonstrated that fusion activity requires the presence of the A59 membrane-spanning domain and the portion of the cys domain that lies upstream of the cytoplasmic tail. The cys domain is a required element since its deletion from the wild-type spike protein abrogates fusion activity. However, addition of the cys domain to fusion-defective chimeric proteins was unable to restore fusion activity. Thus, the cys domain is necessary but is not sufficient to complement the gD-1 anchor and allow for membrane fusion. Site-specific mutations of conserved cysteine residues in the cys domain markedly reduce membrane fusion, which further supports the conclusion that this region is crucial for spike function. The results indicate that the carboxyl-terminus of the spike transmembrane anchor contains at least two distinct domains, both of which are necessary for full membrane fusion.

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Section: Discussionmentioning

confidence: 89%

Coronavirus-Induced Membrane Fusion Requires the Cysteine-Rich Domain in the Spike Protein

2000

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“…Several lines of evidence indicate that the cytoplasmic domain of viral glycoproteins can regulate fusogenicity (32,34,69). In MuLV and equine infectious anemia virus, like that described for M-PMV, the cytoplasmic tail of the TM glycoprotein is further processed by the viral protease after virus particle release, and this process activates Env fusion activity (31,36,37,52,58,76). Truncation of the cytoplasmic tail of lentiviral Env proteins can occur under certain culture conditions (8,35,60).…”

Section: Discussionmentioning

confidence: 96%

Activity of the Mason-Pfizer Monkey Virus Fusion Protein Is Modulated by Single Amino Acids in the Cytoplasmic Tail

Cao

Micoli

Hunter

2005

J Virol

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Mason-Pfizer monkey virus (M-PMV) encodes a transmembrane glycoprotein with a 38-amino-acid-long cytoplasmic tail. After the release of the immature virus, a viral protease-mediated cleavage of the cytoplasmic tail (CT) results in the loss of 17 amino acids from the carboxy terminus and renders the envelope protein fusion competent. To investigate the role of individual amino acid residues in the CT in fusion, a series of mutations was introduced, and the effects of these mutations on glycoprotein biosynthesis and fusion were examined. Most of the alanine-scanning mutations in the CT had little effect on fusion activity. However, four amino acid substitutions (threonine 4, lysine 7, glutamine 9, and isoleucine 10) resulted in substantially increased fusogenicity, while six (leucine 2, phenylalanine 5, isoleucine 13, lysine 16, proline 17, and glycine 31) resulted in much-reduced fusion. Interestingly, the bulk of these mutations are located upstream of the CT cleavage site in a region that has the potential to form a coiled-coil in the Env trimer. Substitutions at glutamine 9 and isoleucine 10 with alanine had the most dramatic positive effect and resulted in the formation of large syncytia. Taken together, these data demonstrate that individual residues within the cytoplasmic domain of M-PMV Env can modulate, in both a positive and negative manner, biological functions that are associated with the extracellular domains of the glycoprotein complex.The glycoprotein complex of retroviruses consists of two polypeptides: the external, highly glycosylated, hydrophilic, surface (SU) glycoprotein and the transmembrane or TM glycoprotein. The glycoproteins are initially translated as a polyprotein precursor from a spliced envelope (env) gene-specific mRNA. The polyprotein precursor Env is proteolytically cleaved during its transport through the Golgi complex to the plasma membrane of the cell (19,28,30,58,75). While Env proteins are not required for the formation of virus particles, they play an important role in the virus replication cycle. The SU glycoprotein is responsible for receptor binding for the virus, whereas the TM glycoprotein is responsible for anchoring the SU protein at the surface of the infected cell or the virus membrane (30,41,48,61). The TM glycoprotein also mediates virus-cell membrane fusion during virus entry as well as cell-cell fusion via a fusion peptide and heptad repeat motifs that are located in the extracellular domain (15,64,72). The two heptad repeat regions located in the TM proteins of viruses such as paramyxovirus (6,9,33,53), influenza virus (73), coronavirus (13, 39), and retroviruses (23, 24) have been shown to play an essential role in viral fusion and infectivity (10,15,25,59,64,70).The glycoproteins of different retroviruses have structural similarity while their sizes and amino acid compositions differ. The amino terminus of the Env precursors contains the signal peptide, a short stretch of hydrophobic amino acids that directs the entry of the newly synthesized env gene protein ...

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“…Other viral fusion proteins and cellular SNARE fusion proteins also require at least one transmembrane anchor. [76][77][78][79][80][81][82][83] Upon completion of fusion, the trimer has reached the conformation seen in the postfusion crystal structures. 29,55,56 The stems (not present in the structures) are docked along the surface of domains II, and the fusion loops and transmembrane anchors lie next to each other in the fused membrane (Fig.…”

Section: Mechanism Of Membrane Fusionmentioning

confidence: 99%

Class II Fusion Proteins

Modis

2013

Advances in Experimental Medicine and Biology

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Enveloped viruses rely on fusion proteins in their envelope to fuse the viral membrane to the host-cell membrane. This key step in viral entry delivers the viral genome into the cytoplasm for replication. Although class II fusion proteins are genetically and structurally unrelated to class I fusion proteins, they use the same physical principles and topology as other fusion proteins to drive membrane fusion. Exposure of a fusion loop first allows it to insert into the host-cell membrane. Conserved hydrophobic residues in the fusion loop act as an anchor, which penetrates only partway into the outer bilayer leaflet of the host-cell membrane. Subsequent folding back of the fusion protein on itself directs the C-terminal viral transmembrane anchor towards the fusion loop. This fold-back forces the host-cell membrane (held by the fusion loop) and the viral membrane (held by the C-terminal transmembrane anchor) against each other, resulting in membrane fusion. In class II fusion proteins, the fold-back is triggered by the reduced pH of an endosome, and is accompanied by the assembly of fusion protein monomers into trimers. The fold-back occurs by domain rearrangement rather than by an extensive refolding of secondary structure, but this domain rearrangement and the assembly of monomers into trimers together bury a large surface area. The energy that is thus released exerts a bending force on the apposed viral and cellular membranes, causing them to bend towards each other and, eventually, to fuse.

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Functional analysis of the cytoplasmic tail of Moloney murine leukemia virus envelope protein

Cited by 90 publications

References 42 publications

Coronavirus-Induced Membrane Fusion Requires the Cysteine-Rich Domain in the Spike Protein

Coronavirus-Induced Membrane Fusion Requires the Cysteine-Rich Domain in the Spike Protein

Activity of the Mason-Pfizer Monkey Virus Fusion Protein Is Modulated by Single Amino Acids in the Cytoplasmic Tail

Class II Fusion Proteins

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