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Structural transition of GP64 triggered by a pH-sensitive multi-histidine switch

Author

Listed:
  • Jinliang Guo

    (ShanghaiTech University)

  • Shangrong Li

    (ShanghaiTech University)

  • Lisha Bai

    (Northwest A&F University)

  • Huimin Zhao

    (ShanghaiTech University)

  • Wenyu Shang

    (ShanghaiTech University)

  • Zhaojun Zhong

    (ShanghaiTech University)

  • Tuerxunjiang Maimaiti

    (ShanghaiTech University)

  • Xueyan Gao

    (ShanghaiTech University)

  • Ning Ji

    (Northwest A&F University)

  • Yanjie Chao

    (Chinese Academy of Sciences)

  • Zhaofei Li

    (Northwest A&F University)

  • Dijun Du

    (ShanghaiTech University)

Abstract

The fusion of viruses with cellular membranes is a critical step in the life cycle of enveloped viruses. This process is facilitated by viral fusion proteins, many of which are conformationally pH-sensitive. The specifics of how changes in pH initiate this fusion have remained largely elusive. This study presents the cryo-electron microscopy (cryo-EM) structures of a prototype class III fusion protein, GP64, in its prefusion and early intermediate states, revealing the structural intermediates accompanying the membrane fusion process. The structures identify the involvement of a pH-sensitive switch, comprising H23, H245, and H304, in sensing the low pH that triggers the initial step of membrane fusion. The pH sensing role of this switch is corroborated by assays of cell-cell syncytium formation and dual dye-labeling. The findings demonstrate that coordination between multiple histidine residues acts as a pH sensor and activator. The involvement of a multi-histidine switch in viral fusion is applicable to fusogens of human-infecting thogotoviruses and other viruses, which could lead to strategies for developing anti-viral therapies and vaccines.

Suggested Citation

  • Jinliang Guo & Shangrong Li & Lisha Bai & Huimin Zhao & Wenyu Shang & Zhaojun Zhong & Tuerxunjiang Maimaiti & Xueyan Gao & Ning Ji & Yanjie Chao & Zhaofei Li & Dijun Du, 2024. "Structural transition of GP64 triggered by a pH-sensitive multi-histidine switch," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51799-4
    DOI: 10.1038/s41467-024-51799-4
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    1. Satinder Kaur & Josue Gomez-Blanco & Ahmad A. Z. Khalifa & Swathi Adinarayanan & Ruben Sanchez-Garcia & Daniel Wrapp & Jason S. McLellan & Khanh Huy Bui & Javier Vargas, 2021. "Local computational methods to improve the interpretability and analysis of cryo-EM maps," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Gabriel Ozorowski & Jesper Pallesen & Natalia de Val & Dmitry Lyumkis & Christopher A. Cottrell & Jonathan L. Torres & Jeffrey Copps & Robyn L. Stanfield & Albert Cupo & Pavel Pugach & John P. Moore &, 2017. "Open and closed structures reveal allostery and pliability in the HIV-1 envelope spike," Nature, Nature, vol. 547(7663), pages 360-363, July.
    3. Yorgo Modis & Steven Ogata & David Clements & Stephen C. Harrison, 2004. "Structure of the dengue virus envelope protein after membrane fusion," Nature, Nature, vol. 427(6972), pages 313-319, January.
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