Molecular basis of the inositol deacylase PGAP1 involved in quality control of GPI-AP biogenesis

Jingjing Hong, Tingting Li, Yulin Chao, Yidan Xu, Zhini Zhu, Zixuan Zhou, Weijie Gu, Qianhui Qu () and Dianfan Li ()
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Jingjing Hong: Chinese Academy of Sciences; University of Chinese Academy of Sciences
Tingting Li: Chinese Academy of Sciences; University of Chinese Academy of Sciences
Yulin Chao: Fudan University
Yidan Xu: Chinese Academy of Sciences; University of Chinese Academy of Sciences
Zhini Zhu: Fudan University
Zixuan Zhou: Fudan University
Weijie Gu: Chinese Academy of Sciences; University of Chinese Academy of Sciences
Qianhui Qu: Fudan University
Dianfan Li: Chinese Academy of Sciences; University of Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract The secretion and quality control of glycosylphosphatidylinositol-anchored proteins (GPI-APs) necessitates post-attachment remodeling initiated by the evolutionarily conserved PGAP1, which deacylates the inositol in nascent GPI-APs. Impairment of PGAP1 activity leads to developmental diseases in humans and fatality and infertility in animals. Here, we present three PGAP1 structures (2.66−2.84 Å), revealing its 10-transmembrane architecture and product-enzyme interaction details. PGAP1 holds GPI-AP acyl chains in an optimally organized, guitar-shaped cavity with apparent energetic penalties from hydrophobic-hydrophilic mismatches. However, abundant glycan-mediated interactions in the lumen counterbalance these repulsions, likely conferring substrate fidelity and preventing off-target hydrolysis of bulk membrane lipids. Structural and biochemical analyses uncover a serine hydrolase-type catalysis with atypical features and imply mechanisms for substrate entrance and product release involving a drawing compass movement of GPI-APs. Our findings advance the mechanistic understanding of GPI-AP remodeling.

Date: 2024
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DOI: 10.1038/s41467-023-44568-2

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