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Non‐canonical proline‐tyrosine interactions with multiple host proteins regulate Ebola virus infection
Author(s) -
Batra Jyoti,
Mori Hiroyuki,
Small Gabriel I,
Anantpadma Manu,
Shtanko Olena,
Mishra Nawneet,
Zhang Mengru,
Liu Dandan,
Williams Caroline G,
Biedenkopf Nadine,
Becker Stephan,
Gross Michael L,
Leung Daisy W,
Davey Robert A,
Amarasinghe Gaya K,
Krogan Nevan J,
Basler Christopher F
Publication year - 2021
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020105658
Subject(s) - library science , st louis , medicine , biology , history , art history , computer science
The Ebola virus VP30 protein interacts with the viral nucleoprotein and with host protein RBBP6 via PPxPxY motifs that adopt non‐canonical orientations, as compared to other proline‐rich motifs. An affinity tag‐purification mass spectrometry approach identified additional PPxPxY‐containing host proteins hnRNP L, hnRNPUL1, and PEG10, as VP30 interactors. hnRNP L and PEG10, like RBBP6, inhibit viral RNA synthesis and EBOV infection, whereas hnRNPUL1 enhances. RBBP6 and hnRNP L modulate VP30 phosphorylation, increase viral transcription, and exert additive effects on viral RNA synthesis. PEG10 has more modest inhibitory effects on EBOV replication. hnRNPUL1 positively affects viral RNA synthesis but in a VP30‐independent manner. Binding studies demonstrate variable capacity of the PPxPxY motifs from these proteins to bind VP30, define PxPPPPxY as an optimal binding motif, and identify the fifth proline and the tyrosine as most critical for interaction. Competition binding and hydrogen‐deuterium exchange mass spectrometry studies demonstrate that each protein binds a similar interface on VP30. VP30 therefore presents a novel proline recognition domain that is targeted by multiple host proteins to modulate viral transcription.