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Structures of liganded glycosylphosphatidylinositol transamidase illuminate GPI-AP biogenesis

Author

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  • Yidan Xu

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

  • Tingting Li

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

  • Zixuan Zhou

    (Fudan University)

  • Jingjing Hong

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

  • Yulin Chao

    (Fudan University)

  • Zhini Zhu

    (Fudan University)

  • Ying Zhang

    (Fudan University)

  • Qianhui Qu

    (Fudan University)

  • Dianfan Li

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

Abstract

Many eukaryotic receptors and enzymes rely on glycosylphosphatidylinositol (GPI) anchors for membrane localization and function. The transmembrane complex GPI-T recognizes diverse proproteins at a signal peptide region that lacks consensus sequence and replaces it with GPI via a transamidation reaction. How GPI-T maintains broad specificity while preventing unintentional cleavage is unclear. Here, substrates- and products-bound human GPI-T structures identify subsite features that enable broad proprotein specificity, inform catalytic mechanism, and reveal a multilevel safeguard mechanism against its promiscuity. In the absence of proproteins, the catalytic site is invaded by a locally stabilized loop. Activation requires energetically unfavorable rearrangements that transform the autoinhibitory loop into crucial catalytic cleft elements. Enzyme-proprotein binding in the transmembrane and luminal domains respectively powers the conformational rearrangement and induces a competent cleft. GPI-T thus integrates various weak specificity regions to form strong selectivity and prevent accidental activation. These findings provide important mechanistic insights into GPI-anchored protein biogenesis.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41281-y
    DOI: 10.1038/s41467-023-41281-y
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    References listed on IDEAS

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    1. Yue Fu & David Estoppey & Silvio Roggo & Dominik Pistorius & Florian Fuchs & Christian Studer & Ashraf S. Ibrahim & Thomas Aust & Frederic Grandjean & Manuel Mihalic & Klaus Memmert & Vivian Prindle &, 2020. "Jawsamycin exhibits in vivo antifungal properties by inhibiting Spt14/Gpi3-mediated biosynthesis of glycosylphosphatidylinositol," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    2. 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.
    3. Yue Fu & David Estoppey & Silvio Roggo & Dominik Pistorius & Florian Fuchs & Christian Studer & Ashraf S. Ibrahim & Thomas Aust & Frederic Grandjean & Manuel Mihalic & Klaus Memmert & Vivian Prindle &, 2020. "Author Correction: Jawsamycin exhibits in vivo antifungal properties by inhibiting Spt14/Gpi3-mediated biosynthesis of glycosylphosphatidylinositol," Nature Communications, Nature, vol. 11(1), pages 1-1, December.
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    Cited by:

    1. 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.
    2. 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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    1. 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.
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