8k9q

Publication Abstract from PubMed

The secretion and quality control of glycosylphosphatidylinositol-anchored proteins (GPI-APs) necessitates post-attachment remodeling initiated by the evolutionarily conserved PGAP1, which deacylates the inositol in nascent GPI-APs. Impairment of PGAP1 activity leads to developmental diseases in humans and fatality and infertility in animals. Here, we present three PGAP1 structures (2.66-2.84 A), revealing its 10-transmembrane architecture and product-enzyme interaction details. PGAP1 holds GPI-AP acyl chains in an optimally organized, guitar-shaped cavity with apparent energetic penalties from hydrophobic-hydrophilic mismatches. However, abundant glycan-mediated interactions in the lumen counterbalance these repulsions, likely conferring substrate fidelity and preventing off-target hydrolysis of bulk membrane lipids. Structural and biochemical analyses uncover a serine hydrolase-type catalysis with atypical features and imply mechanisms for substrate entrance and product release involving a drawing compass movement of GPI-APs. Our findings advance the mechanistic understanding of GPI-AP remodeling.

Molecular basis of the inositol deacylase PGAP1 involved in quality control of GPI-AP biogenesis.,Hong J, Li T, Chao Y, Xu Y, Zhu Z, Zhou Z, Gu W, Qu Q, Li D Nat Commun. 2024 Jan 2;15(1):8. doi: 10.1038/s41467-023-44568-2. PMID:38167496^[1]

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