8imx

Publication Abstract from PubMed

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.

Structures of liganded glycosylphosphatidylinositol transamidase illuminate GPI-AP biogenesis.,Xu Y, Li T, Zhou Z, Hong J, Chao Y, Zhu Z, Zhang Y, Qu Q, Li D Nat Commun. 2023 Sep 8;14(1):5520. doi: 10.1038/s41467-023-41281-y. PMID:37684232^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.