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Structural basis for dimerization of a paramyxovirus polymerase complex

Author

Listed:
  • Jin Xie

    (Lead Discovery, Roche Innovation Center Shanghai)

  • Mohamed Ouizougun-Oubari

    (Boston University Chobanian & Avedisian School of Medicine)

  • Li Wang

    (Infectious Diseases, Roche Innovation Center Shanghai)

  • Guanglei Zhai

    (Lead Discovery, Roche Innovation Center Shanghai)

  • Daitze Wu

    (Infectious Diseases, Roche Innovation Center Shanghai)

  • Zhaohu Lin

    (Lead Discovery, Roche Innovation Center Shanghai)

  • Manfu Wang

    (Wuxi Biortus Biosciences Co. Ltd.)

  • Barbara Ludeke

    (Boston University Chobanian & Avedisian School of Medicine)

  • Xiaodong Yan

    (Wuxi Biortus Biosciences Co. Ltd.)

  • Tobias Nilsson

    (Infectious Diseases, Roche Innovation Center Basel)

  • Lu Gao

    (Infectious Diseases, Roche Innovation Center Shanghai)

  • Xinyi Huang

    (Lead Discovery, Roche Innovation Center Shanghai)

  • Rachel Fearns

    (Boston University Chobanian & Avedisian School of Medicine)

  • Shuai Chen

    (Lead Discovery, Roche Innovation Center Shanghai)

Abstract

The transcription and replication processes of non-segmented, negative-strand RNA viruses (nsNSVs) are catalyzed by a multi-functional polymerase complex composed of the large protein (L) and a cofactor protein, such as phosphoprotein (P). Previous studies have shown that the nsNSV polymerase can adopt a dimeric form, however, the structure of the dimer and its function are poorly understood. Here we determine a 2.7 Å cryo-EM structure of human parainfluenza virus type 3 (hPIV3) L–P complex with the connector domain (CD′) of a second L built, while reconstruction of the rest of the second L–P obtains a low-resolution map of the ring-like L core region. This study reveals detailed atomic features of nsNSV polymerase active site and distinct conformation of hPIV3 L with a unique β-strand latch. Furthermore, we report the structural basis of L–L dimerization, with CD′ located at the putative template entry of the adjoining L. Disruption of the L–L interface causes a defect in RNA replication that can be overcome by complementation, demonstrating that L dimerization is necessary for hPIV3 genome replication. These findings provide further insight into how nsNSV polymerases perform their functions, and suggest a new avenue for rational drug design.

Suggested Citation

  • Jin Xie & Mohamed Ouizougun-Oubari & Li Wang & Guanglei Zhai & Daitze Wu & Zhaohu Lin & Manfu Wang & Barbara Ludeke & Xiaodong Yan & Tobias Nilsson & Lu Gao & Xinyi Huang & Rachel Fearns & Shuai Chen, 2024. "Structural basis for dimerization of a paramyxovirus polymerase complex," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47470-7
    DOI: 10.1038/s41467-024-47470-7
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    References listed on IDEAS

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    Cited by:

    1. Ge Yang & Dong Wang & Bin Liu, 2024. "Structure of the Nipah virus polymerase phosphoprotein complex," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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