Mutational analysis of the leucine zipper-like motif of the human immunodeficiency virus type 1 envelope transmembrane glycoprotein

Chen, Steve S.-L.; Lee, Chun Nan; Lee, William R.; McIntosh, Kenneth; Lee, Tun Hou

doi:10.1128/jvi.67.6.3615-3619.1993

Cited by 109 publications

(77 citation statements)

References 36 publications

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“…However, these same mutations eliminate membrane fusion activity by gp41 (5), a finding that suggests that the HRA mutations may compromise other conformations of the protein. The importance of HRA residues in the membrane fusion activities of HIV gp160 (5,8,15,59), Ebola virus GP (58), and severe acute respiratory syndrome coronavirus S (38) may perhaps suggest that the HRA regions of class I viral fusion proteins may, in general, undergo significant conformational changes during protein refolding. How-ever, determinations of the prefusion structures of these proteins are needed to confirm this hypothesis and reveal whether their HRA regions also adopt spring-loaded conformations analogous to those found in the prefusion structures of paramyxovirus F and influenza virus HA.…”

Section: Discussionmentioning

confidence: 99%

Spring-Loaded Heptad Repeat Residues Regulate the Expression and Activation of Paramyxovirus Fusion Protein

Luque

Russell

2007

J Virol

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During viral entry, the paramyxovirus fusion (F) protein fuses the viral envelope to a cellular membrane. Similar to other class I viral fusion glycoproteins, the F protein has two heptad repeat regions (HRA and HRB) that are important in membrane fusion and can be targeted by antiviral inhibitors. Upon activation of the F protein, HRA refolds from a spring-loaded, crumpled structure into a coiled coil that inserts a hydrophobic fusion peptide into the target membrane and binds to the HRB helices to form a fusogenic hairpin. To investigate how F protein conformational changes are regulated, we mutated in the Sendai virus F protein a highly conserved 10-residue sequence in HRA that undergoes major structural changes during protein refolding. Nine of the 15 mutations studied caused significant defects in F protein expression, processing, and fusogenicity. Conversely, the remaining six mutations enhanced the fusogenicity of the F protein, most likely by helping spring the HRA coil. Two of the residues that were neither located at "a" or "d" positions in the heptad repeat nor conserved among the paramyxoviruses were key regulators of the folding and fusion activity of the F protein, showing that residues not expected to be important in coiled-coil formation may play important roles in regulating membrane fusion. Overall, the data support the hypothesis that regions in the F protein that undergo dramatic changes in secondary and tertiary structure between the prefusion and hairpin conformations regulate F protein expression and activation.

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Section: Discussionmentioning

confidence: 99%

Spring-Loaded Heptad Repeat Residues Regulate the Expression and Activation of Paramyxovirus Fusion Protein

Luque

Russell

2007

J Virol

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“…79, 2005 FUSION ACTIVITY OF EBV gH MUTANTS 12409 protein of Newcastle disease virus) and since this region was conserved in all three gammaherpesviruses analyzed, we decided to examine the importance of this region in EBV gH fusion with epithelial and B cells (11,26). Studies of HIV and other enveloped viruses have shown that hydrophobic residues, especially leucines, located in the coiled coils are important for the proper function of these regions in fusion (5,7,22,36). The putative coiled-coil domain of EBV gH contains four leucines; three of these are also conserved in rhesus and marmoset gH proteins.…”

Section: Location Of a Putative Coiled-coil Domain In Ebv Gh And Consmentioning

confidence: 99%

The Amino Terminus of Epstein-Barr Virus Glycoprotein gH Is Important for Fusion with Epithelial and B Cells

Omerović

Lev

Longnecker

2005

J Virol

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Epstein-Barr virus (EBV) infects B lymphocytes and epithelial cells. While the glycoproteins required forentry into these two cell types differ, the gH/gL glycoprotein complex is essential for entry into both epithelial and B cells. Analysis of gH protein sequences from three gammaherpesviruses (EBV, marmoset, and rhesus) revealed a potential coiled-coil domain in the N terminus. Four leucines located in this region in EBV gH were replaced by alanines by site-directed mutagenesis and analyzed for cell-cell membrane fusion with B cells and epithelial cells. Reduction in fusion activity was observed for mutants containing L65A and/or L69A mutations, while substitutions in L55 and L74 enhanced the fusion activity of the mutant gH/gL complexes with both cell types. All of the mutants displayed levels of cell surface expression similar to those of wild-type gH and interacted with gL and gp42. The observation that a conservative mutation of leucine to alanine in the N terminus of EBV gH results in fusion-defective mutant gH/gL complexes is striking and points to an important role for this region in EBV-mediated membrane fusion with B lymphocytes and epithelial cells. Epstein-Barr virus (EBV) is a gammaherpesvirus that has tropism for both B lymphocytes and epithelial cells (18, 42).Similar to other enveloped viruses, EBV entry into the target cells occurs in two steps: the initial attachment of the virus to the cell surface and the subsequent fusion of the viral envelope and the cell membrane (18, 51). EBV infection can occur by cell-free virus or through cell-cell spread, but fusion is required for both entry pathways (18, 42). The initiation of infection by EBV is driven by interaction of viral glycoproteins with cellsurface receptors (42). EBV encodes as many as 11 glycoproteins, but only a subset is required for efficient EBV entry (15,42). In general, more is known about the mechanism of EBV entry into B lymphocytes than into epithelial cells. Infection of B lymphocytes is initiated by the attachment of glycoprotein gp350/220 to the CD21/CR2 receptor on the B cells (9,43,45). This interaction enhances infection efficiency of B cells, but it is not absolutely required for infection to occur (16). Subsequent to this binding, viral glycoprotein gp42 binds to the B-cell surface protein HLA class II, which triggers fusion mediated by a concerted action of three glycoproteins (gB, gH, and gL) (19,43). The glycoprotein requirement for EBV entry differs between epithelial and B cells; gB, gH, and gL are essential for infection of both epithelial and B cells, while gp42 is required only for B-cell entry (12,20,24,47). Even though gB, gH, and gL are conserved throughout the herpesvirus family, the structure and the exact mechanism of action of these three glycoproteins in the fusion process are still unclear.

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“…This self association may reflect their potential role in stabilizing the fusion attack complex as opposed to their involvement in oligomerization of the "native" envelope. A major support for this argument is that helix-disrupting mutations in the zipper domain fail to influence envelope oligomerization even though they render the envelope fusion incompetent (Dubay et al 1992, Chen et al 1993. indeed, borrowing again from the work of Carr and Kim (Carr & ICim 1993), it would appear that such domains may be unable to interact in the native oligomeric structure of the glycoproteins but, when subjected to certain triggering or activation events (pH drop in the case of the influenza HA), a dramatic conformational change occurs whereby these regions can associate and form coiledcoils.…”

Section: The Leucine Zipper Motif Of Gp41mentioning

confidence: 99%

“…The importance of the two helix motifs of gp41 not only is indicated by the potent anti-HIV activity of peptides and recombinant proteins discussed above but also by the functional assessment of the gp4l mutants (Dubay et al 1992, Chen et al 1993, Cao et al 1993. Of particular interest are the curious results that many non-conservative mutations in the C-terminal helix motif enhance the fusion ability of gp41 (Cao et al 1993) whereas mutations in the leucine zipper region tend to decrease or abolish the fusion activity of gp41 (Dubay et al 1992, Chen et al 1993. A possible explanation for this, consistent with the model presented Fig.…”

Section: Models For Hiv-1-mediated Fusionmentioning

confidence: 99%

Structural Rearrangements in the Transmembrane Glycoprotein after Receptor Binding

Matthews

Wild

Chen

et al. 1994

Immunological Reviews

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Mutational analysis of the leucine zipper-like motif of the human immunodeficiency virus type 1 envelope transmembrane glycoprotein

Cited by 109 publications

References 36 publications

Spring-Loaded Heptad Repeat Residues Regulate the Expression and Activation of Paramyxovirus Fusion Protein

Spring-Loaded Heptad Repeat Residues Regulate the Expression and Activation of Paramyxovirus Fusion Protein

The Amino Terminus of Epstein-Barr Virus Glycoprotein gH Is Important for Fusion with Epithelial and B Cells

Structural Rearrangements in the Transmembrane Glycoprotein after Receptor Binding

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