Structures of liganded glycosylphosphatidylinositol transamidase illuminate GPI-AP biogenesis

Yidan Xu, Tingting Li, Zixuan Zhou, Jingjing Hong, Yulin Chao, Zhini Zhu, Ying Zhang, Qianhui Qu () and Dianfan Li ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41281-y

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