A Peptide Pertaining to the Loop Segment of Human Immunodeficiency Virus gp41 Binds and Interacts with Model Biomembranes: Implications for the Fusion Mechanism

Pascual, R.; Moreno, Miguel; Villalaı́n, José

doi:10.1128/jvi.79.8.5142-5152.2005

Cited by 44 publications

(66 citation statements)

References 56 publications

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“…Peptides composed of the HFP sequence induce fusion between large unilamellar vesicles (LUVs) and between erythrocytes (5,6). There are similar mutation/fusion activity relationships for HFP-induced fusion and HIV-induced fusion which suggests that HFP is a useful model system to understand some aspects of viral/target cell fusion (7-10).There is also evidence for participation of other regions of gp41 in membrane fusion (11)(12)(13)(14).There are atomic-resolution structures of the "soluble ectodomain" of gp41 which does not contain the ∼30 N-terminal residues of gp41 (including the HFP) (2,(15)(16)(17)(18)(19). These structures are believed to correspond to the conformation after fusion has occurred and perhaps during some fusion steps (20).…”

mentioning

confidence: 66%

“…There is also evidence for participation of other regions of gp41 in membrane fusion (11)(12)(13)(14).…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 96%

“…As described in the Supporting Information section, an expression for (ΔS/S 0 ) i cor can be derived: (3) where U C and U N are the fractional abundances of Leu-7 12 CO and Phe-11 14 N, respectively, A C and A N are the fractional 13 …”

Section: Experimental Data Analysismentioning

confidence: 99%

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Conformational Flexibility and Strand Arrangements of the Membrane-Associated HIV Fusion Peptide Trimer Probed by Solid-State NMR Spectroscopy

et al. 2006

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The human immunodeficiency virus (HIV) fusion peptide (HFP) is the N-terminal apolar region of the HIV gp41 fusion protein and interacts with target cell membranes and promotes membrane fusion. The free peptide catalyzes vesicle fusion at least to the lipid mixing stage and serves as a useful model fusion system. For gp41 constructs which lack the HFP, high-resolution structures show trimeric protein and suggest that at least three HFPs interact with the membrane with their C-termini in close proximity. In addition, previous studies have demonstrated that HFPs which are cross-linked at their C-termini to form trimers (HFPtr) catalyze fusion at a rate which is 15−40 times greater than noncross-linked HFP. In the present study, the structure of membrane-associated HFPtr was probed with solid-state nuclear magnetic resonance (NMR) methods. Chemical shift and intramolecular 13 CO-15 N distance measurements show that the conformation of the Leu-7 to Phe-11 region of HFPtr has predominant helical conformation in membranes without cholesterol and β strand conformation in membranes containing ∼30 mol% cholesterol. Interstrand 13 CO-13 CO and 13 CO-15 N distance measurements were not consistent with an in-register parallel strand arrangement but were consistent with either: (1) parallel arrangement with adjacent strands tworesidues out-of-register; or (2) antiparallel arrangement with adjacent strand crossing between Phe-8 and Leu-9. Arrangement (1) could support the rapid fusion rate of HFPtr because of placement of the apolar N-terminal regions of all strands on the same side of the oligomer while arrangement (2) could support the assembly of multiple fusion protein trimers. KeywordsHIV; fusion peptide; cholesterol; membranes; NMR; trimer Enveloped viruses such as human immunodeficiency virus (HIV) are surrounded by a membrane and infect cells through fusion between the viral membrane and the target cell membrane (1,2). This process is mediated by envelope proteins which traverse the viral membrane (3). For HIV, the gp41 envelope protein has a ∼170-residue ectodomain region † This work was supported by NIH award AI47153 to D. P. W. * To whom correspondence should be addressed. Telephone: 517−355−9715. Fax: 517−353−1793. Email: weliky@chemistry.msu.edu.. SUPPORTING INFORMATION AVAILABLE Equations are derived for determination of (ΔS/S 0 ) cor for REDOR and fpCTDQBU analyses. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2008 October 20. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript which lies outside the viral membrane and contains a N-terminal ∼20-residue apolar "fusion peptide" (HFP). The HFP interacts with the target cell membrane and plays an essential role in membrane fusion (4). Peptides composed of the HFP sequence induce fusion between large unilamellar vesicles (LUVs) and between erythrocytes (5,6). There are similar mutation/fusion activity relationships...

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mentioning

confidence: 66%

“…There is also evidence for participation of other regions of gp41 in membrane fusion (11)(12)(13)(14).…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 96%

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Conformational Flexibility and Strand Arrangements of the Membrane-Associated HIV Fusion Peptide Trimer Probed by Solid-State NMR Spectroscopy

et al. 2006

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“…(i) The HIV entry process is considered to be an attractive target for anti-HIV drug design, as blocking HIV entry into target cells leads to prevention of viral infection (6,35). Hence, it is very important to further determine the mechanisms underlying the fusion process to identify new and effective drug targets.…”

Section: Discussionmentioning

confidence: 99%

“…In this model, the Env surface subunit gp120 binds to both CD4 and the chemokine receptor (CCR5 or CXCR4) on the target cells to trigger a conformational change of gp41, i.e. association between its N-and C-terminal heptad repeats (NHR and CHR, respectively) to form a six-helix bundle (6-HB), which is thought to bring the membranes of both virus and target cells into close proximity for facilitating membrane fusion (1,(3)(4)(5)(6). However, the events following 6-HB formation prior to completion of the fusion process are unclear, and the regulation of the fusion process remains to be elucidated.…”

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confidence: 99%

Surface Exposure of the HIV-1 Env Cytoplasmic Tail LLP2 Domain during the Membrane Fusion Process

Zhu

Huang

et al. 2008

Journal of Biological Chemistry

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HIV-1 gp41 cytoplasmic tail (CT) is highly conserved among HIV-1 isolates, particularly the region designated lentivirus lytic peptide (LLP1-2), which includes two ␣-helical domains LLP1 and LLP2. Although the gp41 CT is recognized as a modulator of viral fusogenicity, little is known about the regulatory mechanism of this region in the viral fusion process. Here we report that anti-LLP1-2 and anti-LLP2 antibodies (IgG) inhibited HIV-1 Env-mediated cell fusion and bound to the interface between effector and target cells at a suboptimal temperature (31.5°C), which slows down the fusion process and prolongs the fusion intermediate state. This suggests that LLP1-2, especially the LLP2 region located inside the viral membrane, is transiently exposed on the membrane surface during the fusion process. Synthetic LLP2 peptide could bind to the gp41 six-helix bundle core with high binding affinity. These results suggest that the gp41 CT may interact with the gp41 core, via the surface-exposed LLP2 domain, to regulate Env-mediated membrane fusion.

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The membranotropic regions of the endo and ecto domains of HIV gp41 envelope glycoprotein

Moreno

Giudici

Villalaı́n

2006

Biochimica et Biophysica Acta (BBA) - Biomembranes

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We have identified the membranotropic regions of the full sequence of the HIV gp41 envelope glycoprotein by performing an exhaustive study of membrane rupture, phospholipid-mixing and fusion induced by two 15-mer gp41-derived peptide libraries from HIV strains HIV_MN and HIV_consensus_B on model membranes having different phospholipid compositions. The data obtained for the two strains and its comparison have led us to identify different gp41 membranotropic segments in both ecto- and endodomains which might be implicated in viral membrane fusion and/or membrane interaction. The membranotropic segments corresponding to the gp41 ectodomain were the fusion domain, a stretch located on the N-heptad repeat region adjacent to the fusion domain, part of the immunodominant loop, the pre-transmembrane domain and the transmembrane domain. The membranotropic segments corresponding to the gp41 endodomain were mainly located at some specific parts of the previously described lentivirus lytic sequences. Significantly, the C-heptad repeat region and the Kennedy sequence located in the ectodomain and in the endodomain, respectively, presented no membranotropic activity in any model membrane assayed. The identification of these gp41 segments as well as their membranotropic propensity sustain the notion that different segments of gp41 provide the driving force for the merging of the viral and target cell membranes as well as they help us to define those segments as attractive targets for further development of new anti-viral compounds.

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A Peptide Pertaining to the Loop Segment of Human Immunodeficiency Virus gp41 Binds and Interacts with Model Biomembranes: Implications for the Fusion Mechanism

Cited by 44 publications

References 56 publications

Conformational Flexibility and Strand Arrangements of the Membrane-Associated HIV Fusion Peptide Trimer Probed by Solid-State NMR Spectroscopy

Conformational Flexibility and Strand Arrangements of the Membrane-Associated HIV Fusion Peptide Trimer Probed by Solid-State NMR Spectroscopy

Surface Exposure of the HIV-1 Env Cytoplasmic Tail LLP2 Domain during the Membrane Fusion Process

The membranotropic regions of the endo and ecto domains of HIV gp41 envelope glycoprotein

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