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Title | Molecular basis of the inositol deacylase PGAP1 involved in quality control of GPI-AP biogenesis. |
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Journal, issue, pages | Nat Commun, Vol. 15, Issue 1, Page 8, Year 2024 |
Publish date | Jan 2, 2024 |
Authors | Jingjing Hong / Tingting Li / Yulin Chao / Yidan Xu / Zhini Zhu / Zixuan Zhou / Weijie Gu / Qianhui Qu / Dianfan Li / |
PubMed Abstract | The secretion and quality control of glycosylphosphatidylinositol-anchored proteins (GPI-APs) necessitates post-attachment remodeling initiated by the evolutionarily conserved PGAP1, which deacylates ...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 Å), 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. |
External links | Nat Commun / PubMed:38167496 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.66 - 2.84 Å |
Structure data | EMDB-36995, PDB-8k9q: EMDB-36996, PDB-8k9r: EMDB-36997, PDB-8k9t: |
Chemicals | ChemComp-Y01: ChemComp-D39: ChemComp-MAN: ChemComp-05E: ChemComp-PA1: ChemComp-L9H: ChemComp-PLM: ChemComp-CLR: ChemComp-80Y: ChemComp-LYI: |
Source |
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Keywords | MEMBRANE PROTEIN / Bst1 / Glycosylphosphatidylinositol / GPI anchoring / GPI-AP / GPI-AP remodelase / Integral membrane enzyme / Lipase / Lipid remodeling / Membrane enzyme / Nanodisc / PGAP1 / Transmembrane enzyme / Triad enzyme / TGP / Thermostable green fluorescence protein / Triad enzyme. |