An intrinsically disordered peptide from ebola virus VP35 controls viral RNA synthesis by modulating nucleoprotein-RNA interactions

Daisy W. Leung; Dominika Borek; Priya Luthra; Jennifer M. Binning; Manu Anantpadma; Gai Liu; Ian B. Harvey; Zhaoming Su; Ariel Endlich-Frazier; Juanli Pan; Reed S. Shabman; Wah Chiu; Robert A. Davey; Zbyszek Otwinowski; Christopher F. Basler; Gaya K. Amarasinghe

doi:10.1016/j.celrep.2015.03.034

An intrinsically disordered peptide from ebola virus VP35 controls viral RNA synthesis by modulating nucleoprotein-RNA interactions

Daisy W. Leung, Dominika Borek, Priya Luthra, Jennifer M. Binning, Manu Anantpadma, Gai Liu, Ian B. Harvey, Zhaoming Su, Ariel Endlich-Frazier, Juanli Pan, Reed S. Shabman, Wah Chiu, Robert A. Davey, Zbyszek Otwinowski, Christopher F. Basler, Gaya K. Amarasinghe

Research output: Contribution to journal › Article

74 Scopus citations

Abstract

During viral RNA synthesis, Ebola virus (EBOV) nucleoprotein (NP) alternates between an RNA-template-bound form and a template-free form to provide the viral polymerase access to the RNA template. In addition, newly synthesized NP must be prevented from indiscriminately binding to noncognate RNAs. Here, we investigate the molecular bases for these critical processes. We identify an intrinsically disordered peptide derived from EBOV VP35 (NPBP, residues 20-48) that binds NP with high affinity and specificity, inhibits NP oligomerization, and releases RNA from NP-RNA complexes invitro. The structure of the NPBP/δNP_NTD complex, solved to3.7Å resolution, reveals how NPBP peptide occludes a large surface area that is important for NP-NP and NP-RNA interactions and for viral RNA synthesis. Together, our results identify a highly conserved viral interface that is important for EBOV replication and can be targeted for therapeutic development.

Original language	English (US)
Pages (from-to)	376-389
Number of pages	14
Journal	Cell Reports
Volume	11
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2015.03.034
State	Published - Apr 21 2015

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.celrep.2015.03.034

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Leung, D. W., Borek, D., Luthra, P., Binning, J. M., Anantpadma, M., Liu, G., Harvey, I. B., Su, Z., Endlich-Frazier, A., Pan, J., Shabman, R. S., Chiu, W., Davey, R. A., Otwinowski, Z., Basler, C. F., & Amarasinghe, G. K. (2015). An intrinsically disordered peptide from ebola virus VP35 controls viral RNA synthesis by modulating nucleoprotein-RNA interactions. Cell Reports, 11(3), 376-389. https://doi.org/10.1016/j.celrep.2015.03.034

An intrinsically disordered peptide from ebola virus VP35 controls viral RNA synthesis by modulating nucleoprotein-RNA interactions. / Leung, Daisy W.; Borek, Dominika; Luthra, Priya; Binning, Jennifer M.; Anantpadma, Manu; Liu, Gai; Harvey, Ian B.; Su, Zhaoming; Endlich-Frazier, Ariel; Pan, Juanli; Shabman, Reed S.; Chiu, Wah; Davey, Robert A.; Otwinowski, Zbyszek; Basler, Christopher F.; Amarasinghe, Gaya K.

In: Cell Reports, Vol. 11, No. 3, 21.04.2015, p. 376-389.

Research output: Contribution to journal › Article

Leung, DW, Borek, D, Luthra, P, Binning, JM, Anantpadma, M, Liu, G, Harvey, IB, Su, Z, Endlich-Frazier, A, Pan, J, Shabman, RS, Chiu, W, Davey, RA, Otwinowski, Z, Basler, CF & Amarasinghe, GK 2015, 'An intrinsically disordered peptide from ebola virus VP35 controls viral RNA synthesis by modulating nucleoprotein-RNA interactions', Cell Reports, vol. 11, no. 3, pp. 376-389. https://doi.org/10.1016/j.celrep.2015.03.034

Leung, Daisy W. ; Borek, Dominika ; Luthra, Priya ; Binning, Jennifer M. ; Anantpadma, Manu ; Liu, Gai ; Harvey, Ian B. ; Su, Zhaoming ; Endlich-Frazier, Ariel ; Pan, Juanli ; Shabman, Reed S. ; Chiu, Wah ; Davey, Robert A. ; Otwinowski, Zbyszek ; Basler, Christopher F. ; Amarasinghe, Gaya K. / An intrinsically disordered peptide from ebola virus VP35 controls viral RNA synthesis by modulating nucleoprotein-RNA interactions. In: Cell Reports. 2015 ; Vol. 11, No. 3. pp. 376-389.

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title = "An intrinsically disordered peptide from ebola virus VP35 controls viral RNA synthesis by modulating nucleoprotein-RNA interactions",

abstract = "During viral RNA synthesis, Ebola virus (EBOV) nucleoprotein (NP) alternates between an RNA-template-bound form and a template-free form to provide the viral polymerase access to the RNA template. In addition, newly synthesized NP must be prevented from indiscriminately binding to noncognate RNAs. Here, we investigate the molecular bases for these critical processes. We identify an intrinsically disordered peptide derived from EBOV VP35 (NPBP, residues 20-48) that binds NP with high affinity and specificity, inhibits NP oligomerization, and releases RNA from NP-RNA complexes invitro. The structure of the NPBP/δNPNTD complex, solved to3.7{\AA} resolution, reveals how NPBP peptide occludes a large surface area that is important for NP-NP and NP-RNA interactions and for viral RNA synthesis. Together, our results identify a highly conserved viral interface that is important for EBOV replication and can be targeted for therapeutic development.",

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AU - Anantpadma, Manu

AU - Liu, Gai

AU - Harvey, Ian B.

AU - Su, Zhaoming

AU - Endlich-Frazier, Ariel

AU - Pan, Juanli

AU - Shabman, Reed S.

AU - Chiu, Wah

AU - Davey, Robert A.

AU - Otwinowski, Zbyszek

AU - Basler, Christopher F.

AU - Amarasinghe, Gaya K.

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