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Structures of liganded glycosylphosphatidylinositol transamidase illuminate GPI-AP biogenesis.
- Source :
- Nature Communications; 9/8/2023, Vol. 14 Issue 1, p1-17, 17p
- Publication Year :
- 2023
-
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. [ABSTRACT FROM AUTHOR]
- Subjects :
- GLYCOSYLPHOSPHATIDYLINOSITOL
TRANSMEMBRANE domains
PEPTIDES
PROTEINS
AMIDASES
ENZYMES
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 14
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Nature Communications
- Publication Type :
- Academic Journal
- Accession number :
- 171844930
- Full Text :
- https://doi.org/10.1038/s41467-023-41281-y