Ebola Viral Glycoprotein Bound to Its Endosomal Receptor Niemann-Pick C1

Wang, Han; Shi, Yi; Song, Jian; Qi, Jianxun; Lu, Guangwen; Yan, Jinghua; Gao, George F.

doi:10.1016/j.cell.2015.12.044

Cited by 232 publications

(282 citation statements)

References 62 publications

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“…3a), as demonstrated by the impaired infectivity phenotype of all HR2 mutants (Table 1), and the much lower glycan shielding than at other parts of the viral membrane make HR2 an ideal target for disrupting the HR1-HR2 interaction 23,44,45 . Despite the evolutionary distance among pathogenic viruses, such as the devastating Ebola, HIV and influenza A virus in this study, the structural homology of the trimer-of-hairpins, based on experimentally determined threedimensional structures, may translate into a shared mechanism that hosts can triterpenoids to antagonize membrane fusion in a variety of viruses.…”

Section: Discussionmentioning

confidence: 99%

Triterpenoids Manipulate a Broad Range of Virus-Host Fusion via Wrapping the HR2 Domain Prevalent in Viral Envelopes

Si¹,

Meng²,

Tian³

et al. 2018

Preprint

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Recent years have witnessed a breakthrough in identification of a trimer-ofhairpins motif within viral envelopes that triggers a broad range of virus-host fusion.Identifying a domain capable of controlling virus-host fusion remains a challenge due to sequence diversity, heavy glycan shielding and multiple conformations. Here, we report that HR2, a prevalent heptad repeat sequence comprising an alpha-helical coil anchored in viral membranes, is an accessible site to triterpenes, a class of widely distributed natural products. Triterpenes and their derivatives inhibit the entry of Ebola, HIV, and influenza A viruses with distinct structure-activity relationships. Specifically, triterpenoid probes, upon activation by ultraviolet light, capture the viral envelope via crosslinking the HR2 coil. Profiling the Ebola HR2 sequence using amino acid substitution, surface plasmon resonance (SPR) and nuclear magnetic resonance (NMR) spectroscopy disclosed six constitutive residues that are accessible to triterpenoids, leading to wrapping of the hydrophobic helix by triterpenoids and blocking of the HR1-HR2 interaction, which is critical in the trimer-of-hairpins formation. This finding was also observed in the envelopes of HIV and influenza A viruses and might potentially extend to a broader variety of viruses. Our findings might translate into a shared mechanism that host utilize natural product triterpenoids to antagonize membrane fusion of respective viruses, complementing the current repertoire of antiviral agents.

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Section: Discussionmentioning

confidence: 99%

Triterpenoids Manipulate a Broad Range of Virus-Host Fusion via Wrapping the HR2 Domain Prevalent in Viral Envelopes

Si¹,

Meng²,

Tian³

et al. 2018

Preprint

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“…Also, additional hydrophobic residues (L111, I113, L122, and F225) located in the three-dimensional (3D) model of EBOV GP in close proximity to F88 have been described to be important for interaction with the cellular receptor. A structure of the complex of GP with its endosomal receptor Niemann-Pick C1 (NPC1) indicates that two protruding loops of NPC1 interact with a hydrophobic cavity on the surface of GP (27). This cavity is formed by several amino acid residues, among them V79, P80, T83, W86, G87, and F88.…”

Section: Discussionmentioning

confidence: 99%

Functional Characterization of Adaptive Mutations during the West African Ebola Virus Outbreak

Dietzel

Schudt

Krähling

et al. 2017

J Virol

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The Ebola virus (EBOV) outbreak in West Africa started in December 2013, claimed more than 11,000 lives, threatened to destabilize a whole region, and showed how easily health crises can turn into humanitarian disasters. EBOV genomic sequences of the West African outbreak revealed nonsynonymous mutations, which induced considerable public attention, but their role in virus spread and disease remains obscure. In this study, we investigated the functional significance of three nonsynonymous mutations that emerged early during the West African EBOV outbreak. Almost 90% of more than 1,000 EBOV genomes sequenced during the outbreak carried the signature of three mutations: a D759G substitution in the active center of the L polymerase, an A82V substitution in the receptor binding domain of surface glycoprotein GP, and an R111C substitution in the self-assembly domain of RNA-encapsidating nucleoprotein NP. Using a newly developed virus-like particle system and reverse genetics, we found that the mutations have an impact on the functions of the respective viral proteins and on the growth of recombinant EBOVs. The mutation in L increased viral transcription and replication, whereas the mutation in NP decreased viral transcription and replication. The mutation in the receptor binding domain of the glycoprotein GP improved the efficiency of GP-mediated viral entry into target cells. Recombinant EBOVs with combinations of the three mutations showed a growth advantage over the prototype isolate Makona C7 lacking the mutations. This study showed that virus variants with improved fitness emerged early during the West African EBOV outbreak. IMPORTANCEThe dimension of the Ebola virus outbreak in West Africa was unprecedented. Amino acid substitutions in the viral L polymerase, surface glycoprotein GP, and nucleocapsid protein NP emerged, were fixed early in the outbreak, and were found in almost 90% of the sequences. Here we showed that these mutations affected the functional activity of viral proteins and improved viral growth in cell culture. Our results demonstrate emergence of adaptive changes in the Ebola virus genome during virus circulation in humans and prompt further studies on the potential role of these changes in virus transmissibility and pathogenicity.KEYWORDS West Africa, adaptive mutations, Ebola virus, glycoprotein, zoonotic infections E bola virus (EBOV) belongs to the family Filoviridae in the order Mononegavirales. The Ebola virus disease is characterized by severe fever accompanied by systemic inflammation and damage to the endothelial cell barrier leading to shock and multiorgan failure with high case/fatality rates (1). EBOV particles are filamentous (1 m in length, 80 nm in diameter) and composed of seven viral proteins. The nucleocapsid complex contains the viral RNA encapsidated by nucleoprotein NP and four additional viral proteins. The polymerase complex of VP35 and L is associated with NP via

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“…In addition, NPC1 has been shown to be required for Ebola and Marburg virus entry (23,24) into the cytoplasm, serving as an intraluminal receptor after these viruses have been internalized. Recently a crystal structure of a complex between the middle luminal domain (MLD) of NPC1 and the cleaved glycoprotein (GP) of the Ebola virus has been reported (25,26). Some NPC1 inhibitors can prevent viral infection (27), and the Ebola virus was completely noncontagious in Npc1 −/− mice (28).…”

mentioning

confidence: 99%

Structure of human Niemann–Pick C1 protein

Wang

Coutavas

et al. 2016

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

135

145

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Niemann-Pick C1 protein (NPC1) is a late-endosomal membrane protein involved in trafficking of LDL-derived cholesterol, Niemann-Pick disease type C, and Ebola virus infection. NPC1 contains 13 transmembrane segments (TMs), five of which are thought to represent a "sterol-sensing domain" (SSD). Although present also in other key regulatory proteins of cholesterol biosynthesis, uptake, and signaling, the structure and mechanism of action of the SSD are unknown. Here we report a crystal structure of a large fragment of human NPC1 at 3.6 Å resolution, which reveals internal twofold pseudosymmetry along TM 2-13 and two structurally homologous domains that protrude 60 Å into the endosomal lumen. Strikingly, NPC1's SSD forms a cavity that is accessible from both the luminal bilayer leaflet and the endosomal lumen; computational modeling suggests that this cavity is large enough to accommodate one cholesterol molecule. We propose a model for NPC1 function in cholesterol sensing and transport.endosomal membrane | cholesterol traffic | sterol-sensing domain | crystal structure | allostery C holesterol is a critical component of cellular membranes, and it is either synthesized de novo or supplied from the diet. Although amphiphilic, cholesterol is only poorly soluble in water. Therefore, cholesterol associates with soluble proteins for transport between compartments (1), either as a single molecule or in the form of large lipoprotein particles (2). Cholesterol also functions as a covalently attached ligand in hedgehog-mediated signal transduction (3). Not surprisingly, many proteins involved in cholesterol biosynthesis, transport, or signaling pathways are polytopic, integral membrane proteins (4). Structures of the critical transmembrane region of these polytopic membrane proteins have thus far not been determined, except for an NADPH-dependent reductase in the cholesterol biosynthetic pathway (5), the structure of which yielded insights into the mechanism of intramembrane catalysis.A subgroup of the polytopic integral membrane proteins of cholesterol-related pathways shares a highly conserved region comprised of five transmembrane segments (TMs) that are thought to represent a key regulatory element in response to cholesterol in the bilayer (6). This transmembrane region has been termed the "sterol-sensing domain" (SSD) (7,8). Because crystal structures of these SSDs have not been determined, it has remained unclear precisely how an SSD detects cholesterol in the bilayer and conveys this information to the rest of the protein to influence its activity, stability, or trafficking.Niemann-Pick C1 protein (NPC1) is an SSD-containing, ubiquitous, cholesterol-trafficking protein in the cholesterol uptake pathway (9). Cholesterol is transported throughout the body as cholesterol esters that are packaged into lipoprotein particles including "low-density lipoprotein" (LDL) (2, 10). LDL is endocytosed and transported to late endosomes and lysosomes, where the ∼25-nm particle is subject to lipolysis by lysosomal acid lipase (11,12)...

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Ebola Viral Glycoprotein Bound to Its Endosomal Receptor Niemann-Pick C1

Cited by 232 publications

References 62 publications

Triterpenoids Manipulate a Broad Range of Virus-Host Fusion via Wrapping the HR2 Domain Prevalent in Viral Envelopes

Triterpenoids Manipulate a Broad Range of Virus-Host Fusion via Wrapping the HR2 Domain Prevalent in Viral Envelopes

Functional Characterization of Adaptive Mutations during the West African Ebola Virus Outbreak

Structure of human Niemann–Pick C1 protein

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