Mapping out the intricate relationship of the HIV envelope protein and the membrane environment

Klug, Yoel A.; Rotem, Etai; Schwarzer, Roland; Shai, Yechiel

doi:10.1016/j.bbamem.2016.10.012

Cited by 18 publications

(15 citation statements)

References 212 publications

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“…Significant leakage of contents and lipid mixing was observed upon VL LUV incubation with MPER(671À693) or MPER(671À693)L679I peptides. Interestingly, the TMD(684À704) peptide also induced lipid mixing, an observation consistent with data previously reported in the literature (see for a recent review (48)). Thus, VL vesicle destabilization correlated with the observed virucidal effects of the peptides MPER(671À693) or MPER(671À693)L679I.…”

Section: Resultssupporting

confidence: 91%

Effects of HIV-1 gp41-Derived Virucidal Peptides on Virus-like Lipid Membranes

Carravilla

Cruz

Martin-Ugarte

et al. 2017

Biophysical Journal

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Membrane fusion induced by the envelope glycoprotein enables the intracellular replication of HIV-1; hence, this process constitutes a major target for antiretroviral compounds. It has been proposed that peptides having propensity to interact with membrane interfaces might exert broad antiviral activity against enveloped viruses. To test this hypothesis, in this contribution we have analyzed the antiviral effects of peptides derived from the membrane-proximal external region and the transmembrane domain of the envelope glycoprotein subunit gp41, which display different degrees of interfacial hydrophobicity. Our data support the virucidal activity of a region that combines hydrophobic-at-interface membrane-proximal external region aromatics with hydrophobic residues of the transmembrane domain, and contains the absolutely conserved LWYIK/R sequence, proposed to embody a "cholesterol recognition/interaction amino acid consensus" motif. We further sought to correlate the antiviral activity of these peptides and their effects on membranes that mimic lipid composition and biophysical properties of the viral envelope. The data revealed that peptides endowed with virucidal activity were membrane active and induced permeabilization and fusion of virus-like lipid vesicles. In addition, they modulated lipid packing and miscibility of laterally segregated liquid domains, two properties that depend on the high cholesterol content of the viral membrane. Thus, the overall experimental evidence is consistent with a pattern of HIV inhibition that involves direct alteration of the physical chemistry of the virus membrane. Furthermore, the sequence-dependent effects observed might guide the development of new virucidal peptides.

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Section: Resultssupporting

confidence: 91%

Effects of HIV-1 gp41-Derived Virucidal Peptides on Virus-like Lipid Membranes

Carravilla

Cruz

Martin-Ugarte

et al. 2017

Biophysical Journal

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“…Conformational transition of fusion protein often exposes buried hydrophobic fusion peptide from the core structure. Fusion peptide inserts into the outer leaflet of the plasma membrane of the host cell initiating membrane fusion process [5][6][7][8][9]. Understating fusion mechanism not only garners knowledge of virus pathology but also can be exploited for the development of antiviral drugs [10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

NMR structure and localization of a large fragment of the SARS-CoV fusion protein: Implications in viral cell fusion

Mahajan

Chatterjee

Kannaian

et al. 2018

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The lethal Coronaviruses (CoVs), Severe Acute Respiratory Syndrome-associated Coronavirus (SARS-CoV) and most recently Middle East Respiratory Syndrome Coronavirus, (MERS-CoV) are serious human health hazard. A successful viral infection requires fusion between virus and host cells carried out by the surface spike glycoprotein or S protein of CoV. Current models propose that the S2 subunit of S protein assembled into a hexameric helical bundle exposing hydrophobic fusogenic peptides or fusion peptides (FPs) for membrane insertion. The N-terminus of S2 subunit of SARS-CoV reported to be active in cell fusion whereby FPs have been identified. Atomic-resolution structure of FPs derived either in model membranes or in membrane mimic environment would glean insights toward viral cell fusion mechanism. Here, we have solved 3D structure, dynamics and micelle localization of a 64-residue long fusion peptide or LFP in DPC detergent micelles by NMR methods. Micelle bound structure of LFP is elucidated by the presence of discretely folded helical and intervening loops. The C-terminus region, residues F42-Y62, displays a long hydrophobic helix, whereas the N-terminus is defined by a short amphipathic helix, residues R4-Q12. The intervening residues of LFP assume stretches of loops and helical turns. The N-terminal helix is sustained by close aromatic and aliphatic sidechain packing interactions at the non-polar face. N{H}NOE studies indicated dynamical motion, at ps-ns timescale, of the helices of LFP in DPC micelles. PRE NMR showed that insertion of several regions of LFP into DPC micelle core. Together, the current study provides insights toward fusion mechanism of SARS-CoV.

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“…The Env protein complex of HIV is of utmost biomedical importance because it mediates the contact of the virus with the target cell and assures the fusion of the viral and cellular membranes. Therefore, gp41 or gp120, the building blocks of Env, are prime targets to interfere with the infections cycle of the virus [10,53,54]. Furthermore, a number of broadly neutralizing antibodies have been identified that target conserved regions of the protein complex [55][56][57].…”

Section: Discussionmentioning

confidence: 99%

“…The following fusion events are then driven by gp41 membrane interactions [10], a protein which has received particular attention also in this work (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

“…Fusion intermediates of gp41 are commonly depicted by extended trimers of linear CHR and NHR helices [10,28,29], however, there is increasing evidence that not only the TM domains and the N-terminal fusion peptide [30] but also NHR directly interacts with membranes and actively participates in the fusion process [14,31]. NHR derived peptides have been shown to interact with phospholipid vesicles [14] and the membrane interactions of FP is much increased when covalently linked to NHR [31].…”

Section: Introductionmentioning

confidence: 99%

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Structure, interactions and membrane topology of HIV gp41 ectodomain sequences

Aisenbrey

Bechinger

2020

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The gp41 type I membrane protein is part of the trimeric Env complex forming the spikes at the HIV surface. By interacting with cellular receptors, the Env protein complex initiates the infectious cycle of HIV. After the first contact has been established Env disassembles by shedding gp120 while the remaining gp41 undergoes a number of conformational changes which drive fusion of the cellular and the viral membranes. Here we investigated the membrane interactions and oligomerization of the two gp41 heptad repeat domains NHR and CHR. While these are thought to form a six-helix bundle in the post-fusion state little is known about their structure and role during prior fusion events. When investigated in aqueous buffer by CD and fluorescence quenching techniques the formation of NHR/CHR hetero-oligomers is detected. An equilibrium of monomers and hetero-oligomers is also observed in membrane environments. Furthermore, the partitioning to POPC or POPC/POPG 3/1 vesicles of the two domains alone or in combination has been studied. The membrane interactions were further characterized by 15 N solid-state NMR spectroscopy of uniaxially oriented samples which shows that the polypeptide helices are oriented parallel to the bilayer surface. The 31 P solid-state NMR spectra of the same samples are indicative of considerable disordering of the membrane packing. The data support models where NHR and CHR insert in the viral and cellular membranes, respectively, where they exhibit an active role in the membrane fusion events.

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Mapping out the intricate relationship of the HIV envelope protein and the membrane environment

Cited by 18 publications

References 212 publications

Effects of HIV-1 gp41-Derived Virucidal Peptides on Virus-like Lipid Membranes

Effects of HIV-1 gp41-Derived Virucidal Peptides on Virus-like Lipid Membranes

NMR structure and localization of a large fragment of the SARS-CoV fusion protein: Implications in viral cell fusion

Structure, interactions and membrane topology of HIV gp41 ectodomain sequences

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