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- Title
Structures of liganded glycosylphosphatidylinositol transamidase illuminate GPI-AP biogenesis.
- Authors
Xu, Yidan; Li, Tingting; Zhou, Zixuan; Hong, Jingjing; Chao, Yulin; Zhu, Zhini; Zhang, Ying; Qu, Qianhui; Li, Dianfan
- 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. GPI-T adds GPI to proteins faithfully despite the sequence variance. Here, the authors reveal structural features underpinning this broad specificity, and a fidelity mechanism where unlocking autoinhibition necessitates the synergistic binding of substrate regions with individually weak specificity.
- Subjects
GLYCOSYLPHOSPHATIDYLINOSITOL; TRANSMEMBRANE domains; PEPTIDES; PROTEINS; AMIDASES; ENZYMES
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-41281-y