Early and late HIV-1 membrane fusion events are impaired by sphinganine lipidated peptides that target the fusion site

Klug, Yoel A.; Ashkenazi, Avraham; Viard, Mathias; Porat, Ziv; Blumenthal, Robert; Shai, Yechiel

doi:10.1042/bj20140189

Cited by 13 publications

(10 citation statements)

References 47 publications

(71 reference statements)

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“…These lipids might serve as HIV binding sites or regulate dynamic and clustering of CD4, CCR5 and CXCR4. This information has been recently reinforced by the fact that peptides conjugated to lipid comprising sphingomyelin backbones impair early and late HIV-1 membrane fusion [88].…”

Section: Discussionmentioning

confidence: 99%

Membrane organization of virus and target cell plays a role in HIV entry

2014

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The initial steps of the Human Immunodeficiency Virus (HIV) replication cycle play a crucial role that arbitrates viral tropism and infection efficiency. Before the release of its genome into the host cell cytoplasm, viruses operate a complex sequence of events that take place at the plasma membrane of the target cell. The first step is the binding of the HIV protein envelope (Env) to the cellular receptor CD4. This triggers conformational changes of the gp120 viral protein that allow its interaction with a co-receptor that can be either CCR5 or CXCR4, defining the tropism of the virus entering the cell. This sequential interaction finally drives the fusion of the viral and host cell membrane or to the endocytosis of the viruses. Here, we discuss how the membrane composition and organization of both the virus and the target cell can affect these steps and thus influence the capability of the viruses to infect cells.

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Section: Discussionmentioning

confidence: 99%

Membrane organization of virus and target cell plays a role in HIV entry

2014

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“…However, it may be a daunting task to obtain membrane embedded structures of full-length fusion proteins. To fill the gap, atomic resolution structures and functional analyses, in lipid bilayer or in membrane mimic environments, of FPs are frequently considered [20][21][22][23][24][25][26][27][28].…”

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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“…However, atomic resolution structures of the fulllength fusion proteins in complex with lipid membrane remain a challenging task. In order to infer membrane interactions of fusion processes, fusion peptides are investigated for structural and functional characterization in lipid or membrane mimetic environments [20][21][22][23][24][25][26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

NMR structures and localization of the potential fusion peptides and the pre-transmembrane region of SARS-CoV: Implications in membrane fusion

Mahajan

Bhattacharjya

2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) poses a serious public health hazard. The S2 subunit of the S glycoprotein of SARS-CoV carries out fusion between the virus and the host cells. However, the exact mechanism of the cell fusion process is not well understood. Current model suggests that a conformational transition, upon receptor recognition, of the two heptad core regions of S2 may expose the hydrophobic fusogenic peptide or fusion peptide for membrane insertion. Three regions of the S2 subunit have been proposed to be involved in cell-cell fusion. The N-terminal fusion peptide (FP, residues 770-788), an internal fusion peptide (IFP, residues 873-888) and the pre-transmembrane region (PTM, residues 1185-1202) demonstrated interactions with model lipid membranes and potentially involved in the fusion process. Here, we have determined atomic resolution structures of these three peptides in DPC detergent micelles by solution NMR. FP assumes α-helical conformation with significant distortion at the central Gly residues; enabling a close packing among sidechains of aromatic residues including W, Y and F. The 3-D structure of PMT is characterized by a helix-loop-helix with extensive aromatic interactions within the helices. IFP adopts a rather straight α-helical conformation defined by packing among sidechains of aromatic and aliphatic residues. Paramagnetic spin labeled NMR has demonstrated surface localization of PMT whereas FP and IFP inserted into the micelles. Collectively, data presented in this study will aid in understanding fusion mechanism of SARS-CoV.

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Early and late HIV-1 membrane fusion events are impaired by sphinganine lipidated peptides that target the fusion site

Cited by 13 publications

References 47 publications

Membrane organization of virus and target cell plays a role in HIV entry

Membrane organization of virus and target cell plays a role in HIV entry

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

NMR structures and localization of the potential fusion peptides and the pre-transmembrane region of SARS-CoV: Implications in membrane fusion

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