Structural basis of Nipah and Hendra virus attachment to their cell-surface receptor ephrin-B2

Bowden, Thomas A.; Aricescu, A. Radu; Gilbert, Robert J.C.; Grimes, Jonathan M.; Jones, E Y; Stuart, David I.

doi:10.1038/nsmb.1435

Cited by 197 publications

(299 citation statements)

References 53 publications

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“…2) (27). In the case of the Nipah G RBD, the root mean square deviation (RMSD) between the x-ray structures of its apo and ephrin-bound states is <1 Å (25,26). A similar result also ensues from subjecting these x-ray structures to all-atom molecular dynamics (MD) simulations at physiological temperature (28,29).…”

Section: Introductionmentioning

confidence: 50%

“…4.5.3 (37). Temperature is maintained at 310 K using FIGURE 2 X-ray structures (25,26,58,59) of representative RBDs belonging to the three subfamilies of paramyxovirus receptor binding proteins (HN, H, and G). In each case, the x-ray structure of the receptor-free state (blue) is superimposed over the structure of the receptor-bound state (red), and the RMSDs between the backbone atoms of these structures are indicated.…”

Section: Molecular Dynamicsmentioning

confidence: 99%

“…The receptor binding sites are located in the C-terminal portion of the ectodomain, and are >2 nm away from the F activation site. X-ray crystallography indicates that the C-terminal portion of each of the four monomers of the tetramer fold into separate b-propeller-like structures with central cavities that serve as binding sites for ephrins (25,26). These ephrin (or receptor) binding domains (RBDs) are arranged about each other as a dimer-of-dimers, with the FAD serving as a twofold axis of symmetry (5).…”

Section: Introductionmentioning

confidence: 99%

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Stimulation of Nipah Fusion: Small Intradomain Changes Trigger Extensive Interdomain Rearrangements

Dutta¹,

Siddiqui²,

Botlani³

et al. 2016

Biophysical Journal

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Nipah is an emerging paramyxovirus that is of serious concern to human health. It invades host cells using two of its membrane proteins-G and F. G binds to host ephrins and this stimulates G to activate F. Upon activation, F mediates virus-host membrane fusion. Here we focus on mechanisms that underlie the stimulation of G by ephrins. Experiments show that G interacts with ephrin and F through separate sites located on two different domains, the receptor binding domain (RBD) and the F activation domain (FAD). No models explain this allosteric coupling. In fact, the analogous mechanisms in other paramyxoviruses also remain undetermined. The structural organization of G is such that allosteric coupling must involve at least one of the two interfaces-the RBD-FAD interface and/or the RBD-RBD interface. Here we examine using molecular dynamics the effect of ephrin binding on the RBD-RBD interface. We find that despite inducing small changes in individual RBDs, ephrin reorients the RBD-RBD interface extensively, and in a manner that will enhance solvent exposure of the FAD. While this finding supports a proposed model of G stimulation, we also find from additional simulations that ephrin induces a similar RBD-RBD reorientation in a stimulation-deficient G mutant, V 209 VG / AAA. Together, our simulations suggest that while inter-RBD reorientation may be important, it is not, by itself, a sufficient condition for G stimulation. Additionally, we find that the mutation affects the conformational ensemble of RBD globally, including the RBD-FAD interface, suggesting the latter's role in G stimulation. Because ephrin induces small changes in individual RBDs, a proper analysis of conformational ensembles required that they are compared directly-we employ a method we developed recently, which we now release at SimTK, and show that it also performs excellently for non-Gaussian distributions.

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Section: Introductionmentioning

confidence: 50%

Section: Molecular Dynamicsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Stimulation of Nipah Fusion: Small Intradomain Changes Trigger Extensive Interdomain Rearrangements

Dutta¹,

Siddiqui²,

Botlani³

et al. 2016

Biophysical Journal

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“…Indeed high-resolution structural data are limited to their surface proteins, where crystallographic studies led to the determination of the three-dimensional structure of Henipavirus fusion (F) and attachment (G) proteins (15)(16)(17)(18). As for the N and P proteins, the only available data come from studies carried out by Chan et al (12) and from our recently published studies (14).…”

mentioning

confidence: 99%

Characterization of the Interactions between the Nucleoprotein and the Phosphoprotein of Henipavirus

Habchi

Blangy

Mamelli

et al. 2011

Journal of Biological Chemistry

165

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The Henipavirus genome is encapsidated by the nucleoprotein (N) within a helical nucleocapsid that recruits the polymerase complex via the phosphoprotein (P). In a previous study, we reported that in henipaviruses, the N-terminal domain of the phosphoprotein and the C-terminal domain of the nucleoprotein (N TAIL ) are both intrinsically disordered. Here we show that Henipavirus N TAIL domains are also disordered in the context of full-length nucleoproteins. We also report the cloning, purification, and characterization of the C-terminal X domains (P XD ) of Henipavirus phosphoproteins. Using isothermal titration calorimetry, we show that N TAIL and P XD form a 1:1 stoichiometric complex that is stable under NaCl concentrations as high as 1 M and has a K D in the M range. Using far-UV circular dichroism and nuclear magnetic resonance, we show that P XD triggers an increase in the ␣-helical content of N TAIL . Using fluorescence spectroscopy, we show that P XD has no impact on the chemical environment of a Trp residue introduced at position 527 of the Henipavirus N TAIL domain, thus arguing for the lack of stable contacts between the C termini of N TAIL and P XD . Finally, we present a tentative structural model of the N TAIL -P XD interaction in which a short, order-prone region of N TAIL (␣-MoRE; amino acids 473-493) adopts an ␣-helical conformation and is embedded between helices ␣2 and ␣3 of P XD , leading to a relatively small interface dominated by hydrophobic contacts. The present results provide the first detailed experimental characterization of the N-P interaction in henipaviruses and designate the N TAIL -P XD interaction as a valuable target for rational antiviral approaches.

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“…4). Together with biochemical and structural data of paramyxovirus attachment proteins (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28), a general model of paramyxovirus fusion has been proposed: upon activation by the attachment protein, metastable prefusion F undergoes a series of large-scale, ATP-independent conformational changes, going down an energy gradient from a metastable prefusion state to a highly stable postfusion state. The energy released during F refolding is believed to facilitate membrane fusion to create a pore between the virus and host cell through which the viral ribonucleoprotein complex can enter the target cell.…”

mentioning

confidence: 99%

Immobilization of the N-terminal helix stabilizes prefusion paramyxovirus fusion proteins

Song¹,

Poor²,

Abriata

et al. 2016

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

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Parainfluenza virus 5 (PIV5) is an enveloped, single-stranded, negative-sense RNA virus of the Paramyxoviridae family. PIV5 fusion and entry are mediated by the coordinated action of the receptor-binding protein, hemagglutinin–neuraminidase (HN), and the fusion protein (F). Upon triggering by HN, F undergoes an irreversible ATP- and pH-independent conformational change, going down an energy gradient from a metastable prefusion state to a highly stable postfusion state. Previous studies have highlighted key conformational changes in the F-protein refolding pathway, but a detailed understanding of prefusion F-protein metastability remains elusive. Here, using two previously described F-protein mutations (S443D or P22L), we examine the capacity to modulate PIV5 F stability and the mechanisms by which these point mutants act. The S443D mutation destabilizes prefusion F proteins by disrupting a hydrogen bond network at the base of the F-protein globular head. The introduction of a P22L mutation robustly rescues destabilized F proteins through a local hydrophobic interaction between the N-terminal helix and a hydrophobic pocket. Prefusion stabilization conferred by a P22L-homologous mutation is demonstrated in the F protein of Newcastle disease virus, a paramyxovirus of a different genus, suggesting a conserved stabilizing structural element within the paramyxovirus family. Taken together, the available data suggest that movement of the N-terminal helix is a necessary early step for paramyxovirus F-protein refolding and presents a novel target for structure-based drug design.

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Structural basis of Nipah and Hendra virus attachment to their cell-surface receptor ephrin-B2

Cited by 197 publications

References 53 publications

Stimulation of Nipah Fusion: Small Intradomain Changes Trigger Extensive Interdomain Rearrangements

Stimulation of Nipah Fusion: Small Intradomain Changes Trigger Extensive Interdomain Rearrangements

Characterization of the Interactions between the Nucleoprotein and the Phosphoprotein of Henipavirus

Immobilization of the N-terminal helix stabilizes prefusion paramyxovirus fusion proteins

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