Molecular Insights into Biogenesis of Glycosylphosphatidylinositol Anchor Proteins

Overview

Journal Nat Commun

Specialty Biology

Date 2022 May 13

PMID 35551457

Authors

Yidan Xu

Guowen Jia

Tingting Li

Zixuan Zhou

Yitian Luo

Yulin Chao

Juan Bao

Zhaoming Su

Qianhui Qu

Dianfan Li

Affiliations

Soon will be listed here.

Abstract

Eukaryotic cells are coated with an abundance of glycosylphosphatidylinositol anchor proteins (GPI-APs) that play crucial roles in fertilization, neurogenesis, and immunity. The removal of a hydrophobic signal peptide and covalent attachment of GPI at the new carboxyl terminus are catalyzed by an endoplasmic reticulum membrane GPI transamidase complex (GPI-T) conserved among all eukaryotes. Here, we report the cryo-electron microscopy (cryo-EM) structure of the human GPI-T at a global 2.53-Å resolution, revealing an equimolar heteropentameric assembly. Structure-based mutagenesis suggests a legumain-like mechanism for the recognition and cleavage of proprotein substrates, and an endogenous GPI in the structure defines a composite cavity for the lipid substrate. This elongated active site, stemming from the membrane and spanning an additional ~22-Å space toward the catalytic dyad, is structurally suited for both substrates which feature an amphipathic pattern that matches this geometry. Our work presents an important step towards the mechanistic understanding of GPI-AP biosynthesis.

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