Conformation and Lipid Interaction of the Fusion Peptide of the Paramyxovirus PIV5 in Anionic and Negative-Curvature Membranes from Solid-State NMR

Yao, Hongwei; Hong, Mei

doi:10.1021/ja4121956

Cited by 45 publications

(81 citation statements)

References 84 publications

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“…Thus, higher lipid-chain disorder, with the concomitant increase in the negative membrane curvature, shifts the TMD conformational equilibrium to β-strand. This trend is identical to the response of the FP to lipid unsaturation (11).…”

Section: Piv5 Tmd Changes Its Conformation In Response To the Membranesupporting

confidence: 72%

“…Compared with the FP of the same protein, which converted only a small fraction of the DOPE 31 P spectrum to an isotropic peak (11), the TMD converted most of the intensity to an isotropic peak, indicating that the TMD has stronger curvature-generating ability than the FP. These results counter the prevailing view that viral fusion TMDs are a passive membrane anchor while the FPs are the chief causative agent of bilayer destabilization (36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

“…The TMD is mostly α-helical in both neutral and anionic membranes, and PE is the main trigger for the switch to the β-strand conformation. In comparison, the FP is entirely β-strand in PC and PE membranes and converts to the helical conformation by anionic lipids (11,26). The distinct lipid dependences of FP and TMD structures may enable the intact protein to adapt to different lipid environments of the virus envelope and cell membrane (50).…”

Section: Discussionmentioning

confidence: 99%

“…Cα, Cβ, C′, and 15 N chemical shifts are highly sensitive to backbone (ϕ, ψ) angles (24,25). Because the PIV5 FP structure depends on the membrane environment, including the membrane surface charge, lipid chain unsaturation, and lipid intrinsic curvature (11,26), we measured the TMD chemical shifts in six lipid membranes in the gel-and liquid-crystalline phases, to probe both the rigid-limit structure and the dynamics of the peptide. Two-dimensional 13 C-13 C correlation spectra of the TMD ( Fig.…”

Section: Piv5 Tmd Changes Its Conformation In Response To the Membranementioning

confidence: 99%

“…Extensive spectroscopic studies have shown that influenza, HIV, and paramyxovirus FPs are conformationally plastic and adopt a partially inserted topology in the membrane to induce nonlamellar structures (7)(8)(9)(10)(11). In comparison, little is known about the structures of the C-terminal TMD of viral fusion proteins.…”

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confidence: 99%

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Viral fusion protein transmembrane domain adopts β-strand structure to facilitate membrane topological changes for virus–cell fusion

Yao

Lee

Waring

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The C-terminal transmembrane domain (TMD) of viral fusion proteins such as HIV gp41 and influenza hemagglutinin (HA) is traditionally viewed as a passive α-helical anchor of the protein to the virus envelope during its merger with the cell membrane. The conformation, dynamics, and lipid interaction of these fusion protein TMDs have so far eluded high-resolution structure characterization because of their highly hydrophobic nature. Using magicangle-spinning solid-state NMR spectroscopy, we show that the TMD of the parainfluenza virus 5 (PIV5) fusion protein adopts lipid-dependent conformations and interactions with the membrane and water. In phosphatidylcholine (PC) and phosphatidylglycerol (PG) membranes, the TMD is predominantly α-helical, but in phosphatidylethanolamine (PE) membranes, the TMD changes significantly to the β-strand conformation. Measured order parameters indicate that the strand segments are immobilized and thus oligomerized. 31 P NMR spectra and small-angle X-ray scattering (SAXS) data show that this β-strand-rich conformation converts the PE membrane to a bicontinuous cubic phase, which is rich in negative Gaussian curvature that is characteristic of hemifusion intermediates and fusion pores. 1 H-31 P 2D correlation spectra and 2 H spectra show that the PE membrane with or without the TMD is much less hydrated than PC and PG membranes, suggesting that the TMD works with the natural dehydration tendency of PE to facilitate membrane merger. These results suggest a new viral-fusion model in which the TMD actively promotes membrane topological changes during fusion using the β-strand as the fusogenic conformation.solid-state NMR spectroscopy | small-angle X-ray scattering | conformational polymorphism | membrane curvature | peptide-membrane interactions V iral fusion proteins mediate entry of enveloped viruses into cells by merging the viral lipid envelope and the cell membrane. The membrane-interacting subunit of these glycoproteins contains two hydrophobic domains: a fusion peptide (FP) that is usually located at the N terminus and a transmembrane domain (TMD) at the C terminus (1). Together, these domains sandwich a water-soluble ectodomain with a helical segment that trimerizes into a coiled coil. During virus-cell fusion, the trimeric protein, which initially adopts a compact structure, unfolds to an extended intermediate that exposes the FP to the target cell membrane while keeping the TMD in the virus envelope. This extended conformation then folds onto itself to form a trimer of hairpins, in so doing pulling the cell membrane and the virus envelope into close proximity (2, 3). Subsequently, the FP and TMD are hypothesized to deform the two membranes and dehydrate them (4), eventually causing a fusion pore and a fully merged membrane. In the postfusion state, most viral fusion proteins exhibit a six-helixbundle structure in the ectodomain due to the trimer of hairpins (5).This model of virus-cell fusion largely derives from crystal structures of fusion proteins in the pre-and postfusion st...

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Section: Piv5 Tmd Changes Its Conformation In Response To the Membranesupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Piv5 Tmd Changes Its Conformation In Response To the Membranementioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Viral fusion protein transmembrane domain adopts β-strand structure to facilitate membrane topological changes for virus–cell fusion

Yao

Lee

Waring

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Viral entry mechanisms: the role of molecular simulation in unlocking a key step in viral infections

Valério,

Buga,

Melo

et al. 2024

FEBS Open Bio

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Viral infections are a major global health concern, affecting millions of people each year. Viral entry is one of the crucial stages in the infection process, but its details remain elusive. Enveloped viruses are enclosed by a lipid membrane that protects their genetic material and these viruses are linked to various human illnesses, including influenza, and COVID‐19. Due to the advancements made in the field of molecular simulation, significant progress has been made in unraveling the dynamic processes involved in viral entry of enveloped viruses. Simulation studies have provided deep insight into the function of the proteins responsible for attaching to the host receptors and promoting membrane fusion (fusion proteins), deciphering interactions between these proteins and receptors, and shedding light on the functional significance of key regions, such as the fusion peptide. These studies have already significantly contributed to our understanding of this critical aspect of viral infection and assisted the development of effective strategies to combat viral diseases and improve global health. This review focuses on the vital role of fusion proteins in facilitating the entry process of enveloped viruses and highlights the contributions of molecular simulation studies to uncover the molecular details underlying their mechanisms of action.

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Peptide Structure: Electrophysiological Analysis, Nuclear Magnetic Resonance Analysis, and Molecular Dynamics Simulation of Direct Penetration of Cell‐Penetrating Peptides through Bilayer Lipid Membranes

Izumi¹,

Mijiddorj²,

Saito³

et al. 2022

Cell‐Penetrating Peptides

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Conformation and Lipid Interaction of the Fusion Peptide of the Paramyxovirus PIV5 in Anionic and Negative-Curvature Membranes from Solid-State NMR

Cited by 45 publications

References 84 publications

Viral fusion protein transmembrane domain adopts β-strand structure to facilitate membrane topological changes for virus–cell fusion

Viral fusion protein transmembrane domain adopts β-strand structure to facilitate membrane topological changes for virus–cell fusion

Viral entry mechanisms: the role of molecular simulation in unlocking a key step in viral infections

Peptide Structure: Electrophysiological Analysis, Nuclear Magnetic Resonance Analysis, and Molecular Dynamics Simulation of Direct Penetration of Cell‐Penetrating Peptides through Bilayer Lipid Membranes

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