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The EV71 2A protease occupies the central cleft of SETD3 and disrupts SETD3-actin interaction

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  • Xiaopan Gao

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Bei Wang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Kaixiang Zhu

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Linyue Wang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Bo Qin

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Kun Shang

    (Chinese Academy of Sciences
    Yan’an University)

  • Wei Ding

    (Chinese Academy of Sciences)

  • Jianwei Wang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Sheng Cui

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

Abstract

SETD3 is an essential host factor for the replication of a variety of enteroviruses that specifically interacts with viral protease 2A. However, the interaction between SETD3 and the 2A protease has not been fully characterized. Here, we use X-ray crystallography and cryo-electron microscopy to determine the structures of SETD3 complexed with the 2A protease of EV71 to 3.5 Å and 3.1 Å resolution, respectively. We find that the 2A protease occupies the V-shaped central cleft of SETD3 through two discrete sites. The relative positions of the two proteins vary in the crystal and cryo-EM structures, showing dynamic binding. A biolayer interferometry assay shows that the EV71 2A protease outcompetes actin for SETD3 binding. We identify key 2A residues involved in SETD3 binding and demonstrate that 2A’s ability to bind SETD3 correlates with EV71 production in cells. Coimmunoprecipitation experiments in EV71 infected and 2A expressing cells indicate that 2A interferes with the SETD3-actin complex, and the disruption of this complex reduces enterovirus replication. Together, these results reveal the molecular mechanism underlying the interplay between SETD3, actin, and viral 2A during virus replication.

Suggested Citation

  • Xiaopan Gao & Bei Wang & Kaixiang Zhu & Linyue Wang & Bo Qin & Kun Shang & Wei Ding & Jianwei Wang & Sheng Cui, 2024. "The EV71 2A protease occupies the central cleft of SETD3 and disrupts SETD3-actin interaction," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48504-w
    DOI: 10.1038/s41467-024-48504-w
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    1. Alex W. Wilkinson & Jonathan Diep & Shaobo Dai & Shuo Liu & Yaw Shin Ooi & Dan Song & Tie-Mei Li & John R. Horton & Xing Zhang & Chao Liu & Darshan V. Trivedi & Katherine M. Ruppel & José G. Vilches-M, 2019. "SETD3 is an actin histidine methyltransferase that prevents primary dystocia," Nature, Nature, vol. 565(7739), pages 372-376, January.
    2. Christine E. Peters & Ursula Schulze-Gahmen & Manon Eckhardt & Gwendolyn M. Jang & Jiewei Xu & Ernst H. Pulido & Conner Bardine & Charles S. Craik & Melanie Ott & Or Gozani & Kliment A. Verba & Ruth H, 2022. "Structure-function analysis of enterovirus protease 2A in complex with its essential host factor SETD3," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
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