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Molecular insights into biogenesis of glycosylphosphatidylinositol anchor proteins

Author

Listed:
  • Yidan Xu

    (University of CAS, Chinese Academy of Sciences (CAS))

  • Guowen Jia

    (Sichuan University)

  • Tingting Li

    (University of CAS, Chinese Academy of Sciences (CAS))

  • Zixuan Zhou

    (Fudan University)

  • Yitian Luo

    (University of CAS, Chinese Academy of Sciences (CAS)
    ShanghaiTech University)

  • Yulin Chao

    (Fudan University)

  • Juan Bao

    (University of CAS, Chinese Academy of Sciences (CAS))

  • Zhaoming Su

    (Sichuan University)

  • Qianhui Qu

    (Fudan University)

  • Dianfan Li

    (University of CAS, Chinese Academy of Sciences (CAS))

Abstract

Eukaryotic cells are coated with an abundance of glycosylphosphatidylinositol anchor proteins (GPI-APs) that play crucial roles in fertilization, neurogenesis, and immunity. The removal of a hydrophobic signal peptide and covalent attachment of GPI at the new carboxyl terminus are catalyzed by an endoplasmic reticulum membrane GPI transamidase complex (GPI-T) conserved among all eukaryotes. Here, we report the cryo-electron microscopy (cryo-EM) structure of the human GPI-T at a global 2.53-Å resolution, revealing an equimolar heteropentameric assembly. Structure-based mutagenesis suggests a legumain-like mechanism for the recognition and cleavage of proprotein substrates, and an endogenous GPI in the structure defines a composite cavity for the lipid substrate. This elongated active site, stemming from the membrane and spanning an additional ~22-Å space toward the catalytic dyad, is structurally suited for both substrates which feature an amphipathic pattern that matches this geometry. Our work presents an important step towards the mechanistic understanding of GPI-AP biosynthesis.

Suggested Citation

  • Yidan Xu & Guowen Jia & Tingting Li & Zixuan Zhou & Yitian Luo & Yulin Chao & Juan Bao & Zhaoming Su & Qianhui Qu & Dianfan Li, 2022. "Molecular insights into biogenesis of glycosylphosphatidylinositol anchor proteins," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30250-6
    DOI: 10.1038/s41467-022-30250-6
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    References listed on IDEAS

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    Cited by:

    1. Yidan Xu & Tingting Li & Zixuan Zhou & Jingjing Hong & Yulin Chao & Zhini Zhu & Ying Zhang & Qianhui Qu & Dianfan Li, 2023. "Structures of liganded glycosylphosphatidylinositol transamidase illuminate GPI-AP biogenesis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Jingjing Hong & Tingting Li & Yulin Chao & Yidan Xu & Zhini Zhu & Zixuan Zhou & Weijie Gu & Qianhui Qu & Dianfan Li, 2024. "Molecular basis of the inositol deacylase PGAP1 involved in quality control of GPI-AP biogenesis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Xiaoqiong Wei & You Lu & Liangguang Leo Lin & Chengxin Zhang & Xinxin Chen & Siwen Wang & Shuangcheng Alivia Wu & Zexin Jason Li & Yujun Quan & Shengyi Sun & Ling Qi, 2024. "Proteomic screens of SEL1L-HRD1 ER-associated degradation substrates reveal its role in glycosylphosphatidylinositol-anchored protein biogenesis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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