Structures of liganded glycosylphosphatidylinositol transamidase illuminate GPI-AP biogenesis.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 09 2023
08 09 2023
Historique:
received:
25
04
2023
accepted:
25
08
2023
medline:
11
9
2023
pubmed:
9
9
2023
entrez:
8
9
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37684232
doi: 10.1038/s41467-023-41281-y
pii: 10.1038/s41467-023-41281-y
pmc: PMC10491789
doi:
Substances chimiques
transamidases
EC 2.3.2.-
Glycosylphosphatidylinositols
0
Aminoacyltransferases
EC 2.3.2.-
Ligands
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5520Informations de copyright
© 2023. Springer Nature Limited.
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