| Autor: |
Xu, Yidan, Li, Tingting, Zhou, Zixuan, Hong, Jingjing, Chao, Yulin, Zhu, Zhini, Zhang, Ying, Qu, Qianhui, Li, Dianfan |
| Předmět: |
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| Zdroj: |
Nature Communications; 9/8/2023, Vol. 14 Issue 1, p1-17, 17p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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