TY - JOUR
T1 - An intrinsically disordered peptide from ebola virus VP35 controls viral RNA synthesis by modulating nucleoprotein-RNA interactions
AU - Leung, Daisy W.
AU - Borek, Dominika
AU - Luthra, Priya
AU - Binning, Jennifer M.
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.
N1 - Funding Information:
We thank Drs. T. Ellenberger, D. Fremont, T. Brett, N. Tolia, W. Li, and J. Payton for discussions; members of the G.K.A./G.L. W.C., C.F.B., and R.A.D. laboratories for experimental support; and Drs. S. Ginell, N. Duke, and J. Lazarz at Advanced Photon Source (APS) Sector 19 for beamline access and assistance during data collection. Use of Structural Biology Center beamlines at the APS is supported by the US DOE under contract DE-AC02-06CH11357. Use of the National Magnetic Resonance Facility at Madison is supported by NIH grant P41GM103399. This work was supported in part by a contract to the Center for Structural Genomics of Infectious Diseases (CSGID) from the NIAID/NIH/DHS (contract number HHSN272201200026C, Anderson-PI) to Z.O., by DOD grants DTRA 1-21-1-0002 to R.A.D., DTRA-HDTRA1-12-1-0051 and DTRA HDTRA1-14-1-0013 to C.F.B. and G.K.A., and by NIH grants (R01AI107056 to D.W.L.; R01GM053163 to Z.O.; R01AI077519 to R.A.D.; R01AI059536 to C.F.B.; U19AI109945 [Basler-PI] to C.F.B., D.W.L., and G.K.A.; and U19AI109664 [Basler-PI] to D.W.L., D.B., C.F.B. and G.K.A.; U19 AI070489 [Holtzman-PI], P41GM103832, and P50 GM1003297 to W.C.; and R01AI081914 to G.K.A.).
PY - 2015/4/21
Y1 - 2015/4/21
N2 - 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 to3.7Å 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.
AB - 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 to3.7Å 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.
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U2 - 10.1016/j.celrep.2015.03.034
DO - 10.1016/j.celrep.2015.03.034
M3 - Article
C2 - 25865894
AN - SCOPUS:84928208144
VL - 11
SP - 376
EP - 389
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 3
ER -