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Journal of Virology, October 2006, p. 9921-9925, Vol. 80, No. 19
0022-538X/06/$08.00+0     doi:10.1128/JVI.00380-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Receptor-Triggered but Alkylation-Arrested Env of Murine Leukemia Virus Reveals the Transmembrane Subunit in a Prehairpin Conformation

Michael Wallin, Maria Ekström, and Henrik Garoff^*

Department of Biosciences at Novum, Karolinska Institute, S-141 57 Huddinge, Sweden

Received 23 February 2006/ Accepted 14 July 2006

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A central feature of the prevailing model for retrovirus fusion is conversion of the transmembrane (TM) subunit from a prehairpin to a hairpin-like structure. The fusion inhibition of many retroviruses, except murine leukemia virus (MLV), with peptides corresponding to interacting regions in the hairpin supports the model. MLV fusion is controlled by isomerization of the intersubunit disulfide in Env. We show here that TM peptides bind to MLV Env that has been arrested at an intermediate stage of activation by alkylation of the isomerization-active thiol in the surface subunit. This inhibits fusion rescue by dithiothreitol-mediated reduction of the surface protein-TM disulfide.

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The fusion activation mechanism of retrovirus Env is thought to resemble that of influenza virus hemagglutinin (24). Thus, cleavage of the trimeric Env precursor in the infected cell is postulated to generate a metastable state in the TM subunit, which is maintained by interaction with the SU subunit (11). When the virus binds to its cell receptor via the surface protein (SU), the SU-transmembrane protein (TM) interaction will be weakened so that TM can refold into a stable conformation. This occurs in two steps. First TM inserts its fusion peptide into the target membrane. Then it folds back on itself and forces the target and the viral membranes together for fusion. The corresponding TM conformations are called prehairpin and a hairpin, respectively.

This model is supported by structural analyses of fusion protein ectodomain fragments, which have revealed the TM fragments as a trimer of hairpins (3, 5, 6, 14, 28). The N-terminal parts downstream of the fusion peptide form an internal coiled coil of -helices, and the C-terminal parts pack into its intersubunit grooves in an antiparallel orientation. The model is reinforced by functional studies. Peptides corresponding to the interacting regions in the TM hairpin inhibit fusion of human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus, feline immunodeficiency virus, human T-cell leukemia virus, and avian sarcoma and leukosis virus (2, 4, 7, 10, 12, 13, 15, 16, 18, 19, 20, 22, 29, 30). As inhibition requires prior receptor triggering of Env, activation probably involves transient exposure of a trimeric prehairpin structure. Surprisingly, TM peptides of Moloney murine leukemia virus (Mo-MLV) Env have failed to inhibit membrane fusion (21). This could be because of sterically or kinetically restricted exposure of a TM-prehairpin intermediate or weak binding or because Mo-MLV does not follow the canonical activation pathway.

The fusion activity of Mo-MLV Env is controlled by isomerization of its intersubunit disulfide bond (26, 27). The TM-bridging Cys in SU is part of an isomerization-active motif, Cys-X-X-Cys (CXXC), where the other Cys carries a free thiol. Receptor-binding activates the thiol to attack the intersubunit disulfide and rearrange it into a disulfide isomer within the motif. This results in SU dissociation and activation of the fusion-promoting conformational changes in TM. However, triggering in the presence of a membrane-impermeable alkylator, 4-(N-maleimido)benzyl--trimethylammonium iodide (M135), modifies the CXXC thiol and blocks isomerization. Consequently, Env will be arrested at an intermediate stage of its conformational transition (the isomerization-arrested stage [IAS]) and no fusion commences. The arrest can be relieved by dithiothreitol (DTT) reduction of the intersubunit disulfide. In this study, we have compared the alkylated, activation-arrested Env of Mo-MLV with nonarrested Env as a target for potentially fusing-inhibiting TM peptides. The rationale was that arrested Env might expose matching regions for the added peptides more favorably than nonarrested Env. If peptides bind, they should inhibit DTT-released fusion of the alkylated virus.

Of the peptides tested, one spanned the N-terminal helix downstream of the fusion peptide in TM (the N-helix peptide Asp515-Leu547), the second was a 32-residue region downstream of the point of chain reversal in activated TM, including a predicted helix (the C-helix peptide Phe564-Gly595), the third was a 25-residue region within the C-helix peptide (the short C-helix peptide His568-Ser592), and the fourth was a 25-residue region adjacent to the membrane anchor of TM (the anchor-flanking peptide Gln585-Thr609) (Fig. 1A) (6, 14). N-acetylated and C-amidated peptides were synthesized on a solid-phase support and purified (95%) by reverse-phase high-pressure liquid chromatography (Alpha Diagnostics International, San Antonio, TX). Predetermined amounts were taken up into 50 µl of 20% acetic acid and diluted to 500 µl (500 µM) with water. Peptide concentrations were verified spectrophotometrically.

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FIG. 1. (A) Mo-MLV TM peptides used in this study. The functional and structural regions of the Mo-MLV TM subunit are indicated in the top bar. The synthesized peptides are shown below as short bars corresponding to their location in the TM polypeptide. The N- and C-terminal amino acids of the TM subunit and the peptides are indicated, as are the amino acid sequences of the peptides. The residues in bold were changed in N-helix and anchor-flanking variant peptides used as controls (Leu530Pro, Trp596Ala, and Trp606Ala). (B) Peptide inhibition of DTT-released fusion of Mo-MLV at IAS. XC cell-bound Mo-MLV was chased into IAS by incubation for 15 min at 37°C in TN-Ca2+ with 0.8 mM M135. The cultures were then incubated in TN-Ca2+ without M135 but with TM peptides at the indicated concentrations for 10 min at 20°C. The fusion arrest was released by DTT treatment for 2 min at 37°C. Residual virus on the cell surface was inactivated with pH 3 buffer, and the cultures were further incubated in culture medium at 37°C for 3 h. Fusion efficiencies were estimated by the extent of virus-induced polykaryon formation and are given as percentages of the fusion of a control sample incubated without peptide (± the standard deviations, n = 10). (C) Peptide inhibition of nonarrested Mo-MLV fusion. XC cell-bound Mo-MLV was incubated with peptides at the indicated concentrations first for 15 min at 37°C and then for 10 min at 20°C. Residual virus on the cell surface was inactivated, and fusion efficiencies were estimated as previously described (± the standard deviations, n = 10).

We first studied the effect of peptides on the DTT-released fusion of alkylation-arrested virus. Mo-MLV in Mov-3 cell culture medium was bound to receptor-positive rat XC cells for 1 h at 4°C and then incubated in TN (17 mM Tris, 8 mM HEPES, 150 mM NaCl, pH 7.4)-Ca²⁺ (1.8 mM) at 37°C for 15 min in the presence of a 0.8 mM concentration of the alkylator M135 to chase all receptor-bound Env proteins into the IAS (26, 27). The alkylator was washed off, and the fusion-arrested virus was incubated in TN-Ca²⁺ for 10 min at 20°C in the presence of 0 to 50 µM peptide. The arrested stage was released by adding DTT to 20 mM and incubating the mixture for 2 min at 37°C. Nonpenetrated virus was inactivated by 1 min of incubation at 20°C in pH 3 buffer, and virus-induced cell-cell fusion (fusion from without) was assessed by polykaryon formation after an additional incubation for 3 h at 37°C in medium as previously described (26). The N-helix and the anchor-flanking peptides were found to be inhibitory, but the C-helix and the short C-helix peptides were not (Fig. 1B). Relative to the peptide-lacking control, 85% inhibition was achieved with 50 µM N-helix or anchor-flanking peptide. The 50% inhibitory concentrations of the two peptides were 20 and 25 µM. Interestingly, the fusion rescue was significantly more resistant to the anchor-flanking peptide than to the N-helix peptide at lower peptide concentrations.

We next analyzed the effect of peptides on nonarrested fusion. Cell-bound virus was incubated in TN-Ca²⁺ containing 0 to 50 µM peptide, first for 15 min at 37°C and then for 10 min at 20°C. Nonfused virus was inactivated, and fusion was measured as already described. The results were similar to the peptide effects on the DTT-rescued fusion of arrested virus, although the inhibiting effects of the N-helix and the anchor-flanking peptides were much lower (maximally about 35%) (Fig. 1C). A longer incubation (20 min) with peptide at 37°C did not increase the inhibition.

It was possible that the limited effects of the N-helix and the anchor-flanking peptides on the fusion of nonarrested virus were due to peptide binding to its native rather than its triggered state. To find out, Mo-MLV in culture medium was dialyzed (Slide-A-Lyzer, 3.5-kDa molecular mass cutoff; Pierce Co., Rockford, IL) against HN-Ca²⁺ (15 mM HEPES, 150 mM NaCl, 1.8 mM Ca²⁺, pH 7.4) at 4°C for 24 h and, after adjusting the buffer to TN-Ca²⁺, incubated with the respective peptide at 50 µM or without it for 15 min at 37°C and additionally for 10 min at 20°C. The pretreated virus was then bound to XC cells for 1 h on ice, free peptide was washed off, and fusion was activated by incubation first for 15 min at 37°C and then for 10 min at 20°C. The subsequent analyses of virus-induced polykaryon formation showed that pretreatment of the virus with either peptide had no significant effect on its fusion activity (data not shown).

The specificity of the inhibitory effect of the N-helix peptide was tested with a variant where Pro replaced Leu530 (Fig. 1A). This should terminate the -helix, as suggested before (21), and probably inactivate the peptide. An anchor-flanking peptide variant was made by changing its two Trp residues into Ala. Trp residues appear to cluster in this region of viral membrane fusion proteins and function in fusion (8, 23, 25). When tested in the DTT-mediated fusion release assay of alkylation-arrested Env, both peptide variants were found to be inactive (Fig. 2A and B). This suggested that the peptides targeted the TM subunit. This was supported by the finding that pretreatment of XC cells with the N-helix or the anchor-flanking peptide at 50 µM (15 min at 37°C plus 10 min at 20°C) retained their competence for virus-induced cell-cell fusion (data not shown).

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FIG. 2. Specificity of peptide inhibition. Cell-bound virus was chased into IAS as described in the legend to Fig. 1B. The cultures were then incubated for 10 min at 20°C in the presence of N-helix or variant N-helix peptide (Leu530Pro) (A) and anchor-flanking or variant anchor-flanking peptide (Trp596Ala, Trp606Ala) (B) at the indicated concentrations. The IAS was relieved by DTT treatment, and fusion efficiencies were measured as already described. Fusion efficiencies are given as percentages of the fusion efficiency without peptide (± the standard deviations, n = 6).

Earlier we showed that the fusion of Mo-MLV can be reversibly arrested by lauryl-lysophosphatidylcholine (LPC) (the lipid-arrested state [LAS]) (27). In this study, we tested whether it is possible to inhibit fusion release from Mo-MLV at LAS if the fusion-arrested virus as been treated with TM peptides. To this end, XC cell-bound Mo-MLV was incubated in TN-Ca²⁺ for 15 min at 37°C in the presence or absence of 1 mM LPC and 50 µM N-helix or anchor-flanking peptide. The LPC was removed by four swift washes with TN-Ca²⁺, and the residual fusion capacity was released by incubation for 20 min at 37°C in TN-Ca²⁺. The remaining virus on the cell surface was inactivated with pH 3 buffer, and the cells were processed for polykaryon formation. We confirmed that the LPC treatment reversibly arrested the fusion of Mo-MLV (Fig. 3, columns 2 and 3) (27). However, neither of the peptides had any significant inhibitory effect on fusion release in virus at LAS (Fig. 3, columns 4 and 5). It remained possible that the peptides were bound at fusion arrest but removed during the washes preceding reactivation. Therefore, we analyzed the effects of the peptides (50 µM) on the DTT-released fusion of M135-arrested virus that had been subjected to four washes with TN-Ca²⁺ and an additional 10-min incubation in TN-Ca²⁺ at 37°C after the alkylation and peptide treatments. The analyses showed that the additional treatments did not decrease the effects of the two peptides in this assay (data not shown).

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FIG. 3. TM peptides cannot inhibit fusion released from lipid-arrested virus. Cell-bound virus was incubated in TN-Ca2+ for 15 min at 37°C in the presence or absence of 1 mM LPC and 50 µM N-helix or anchor-flanking peptide (as indicated) (first incubation). The LPC was removed by four swift washes, and fusion was released by incubation for 20 min at 37°C in TN-Ca2+ without peptide (second incubation). Fusion efficiencies were measured as already described and are given as percentages of that of the virus sample incubated in the absence of LPC and peptide (column 1) (± the standard deviations, n = 3).

Altogether, our present results show that activated Mo-MLV Env displays an apparent prehairpin structure of TM, the back folding of which can be prevented by externally added N-helix peptide. The inhibition was less evident in a nonarrested fusion, but if the conformational transition of receptor-triggered Env was interrupted by alkylating the emerging isomerization-active CXXC-thiol, the prehairpin structure remained exposed and efficient N-helix peptide binding became possible. The 50% inhibitory concentration of the Mo-MLV TM N-helix peptide (20 µM) was similar to that of the corresponding HIV-1 gp41 peptide (16 µM) (2). Native virus or virus at LAS was resistant to peptide inhibition, suggesting that the N peptide binds to a conformational intermediate of Env. This is similar to the HIV-1 gp41 and avian leukosis virus TM peptides. In both cases, inhibition required prior triggering of the virus by the receptor and in the case of avian leukosis virus, but not HIV-1, the LAS was found to be resistant to peptide inhibition (7, 17, 19, 20).

N-helix peptide monomers might inhibit the fusion of nonarrested virus by interfering with the formation of the trimeric coiled-coil prehairpin structure of TM. The effect might be limited by peptide trimerization above 5 µM and the rapid back-folding kinetics of TM, which would restrict the binding of the trimers to the C-terminal region of the TM ectodomain. However, alkylated, isomerization-blocked Env apparently remains in an open prehairpin conformation exposing the C-terminal region for N-helix peptide trimers. Thus, the sensitivity of Mo-MLV fusion to externally added TM N peptides resembles that of HIV-1 with cytoplasmically truncated gp41 toward gp41 C peptides. The fusion of the HIV-1 variant was, in contrast to that of wild-type HIV-1, resistant to C peptide inhibition, if not arrested by decreased temperature at an early stage in its fusion activation pathway (1).

The complete lack of inhibitory activity of the C-helix peptides in nonarrested Mo-MLV fusion confirms earlier findings (21). The lack of activity also in the DTT-released fusion of alkylation-arrested virus suggests that the C peptides interact only weakly, if at all, with the N-terminal coiled coil. Possibly, the free C peptides cannot obtain a binding-facilitating conformation. The fusion-inhibitory mechanism of the anchor-flanking peptide might be related to the multi-Trp(Phe) motif that is found in this region of retrovirus TM subunits (25). Violation of the motif in HIV-1 by mutagenesis inhibits Env-mediated fusion (23), and corresponding peptides inhibit infection with feline immunodeficiency virus (8, 23). The aromatic motif might direct the anchor-flanking peptides of the TM subunits to the external membrane-water interphase, where they might interact with the fusion peptide region of TM (9, 31). Indeed, the HIV-1 Env anchor-flanking peptide possesses membrane-perturbing properties, like the fusion peptide, and interacts with the latter in solution (25). Our present results show that the target for the Mo-MLV anchor-flanking peptide is accessible not in the native virus but first in the receptor-triggered alkylation-arrested intermediate structure of Env. This is consistent with a model according to which the TM subunit of the latter exposes not only a prehairpin structure but also a fusion peptide in the target membrane while still maintaining receptor contact via the intersubunit disulfide-shackled SU.

 
We acknowledge Mathilda Sjöberg for helpful discussions and critical reading of the manuscript.

Swedish Science Foundation grant 2778 and Swedish Cancer Foundation grant 0525 to H.G. supported this work.

 
* Corresponding author. Mailing address: Department of Biosciences at Novum, Karolinska Institute, S-141 57 Huddinge, Sweden. Phone: 46-8-6089125. Fax: 46-8-7745538. E-mail: henrik.garoff{at}cbt.ki.se.

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Journal of Virology, October 2006, p. 9921-9925, Vol. 80, No. 19
0022-538X/06/$08.00+0     doi:10.1128/JVI.00380-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

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• Sjoberg, M., Lindqvist, B., Garoff, H. (2008). Stabilization of TM Trimer Interactions during Activation of Moloney Murine Leukemia Virus Env. J. Virol. 82: 2358-2366 [Abstract] [Full Text]  

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