Distinct Mechanisms for Processing Autophagy Protein LC3-PE by RavZ and ATG4B.

Chembiochem : a European Journal of Chemical Biology
Aimin YangYao-Wen Wu

Abstract

Autophagy is a conserved catabolic process involved in the elimination of proteins, organelles and pathogens in eukaryotic cells. Lipidated LC3 proteins that are conjugated to phosphatidylethanolamine (PE) play a key role in autophagosome biogenesis. Endogenous ATG4-mediated deconjugation of LC3-PE is required for LC3 recycling. However, the Legionella effector RavZ irreversibly deconjugates LC3-PE to inhibit autophagy. It is not clear how ATG4 and RavZ process LC3-PE with distinct modes. Herein, a series of semisynthetic LC3-PE proteins containing C-terminal mutations or insertions were used to investigate the relationship of the C-terminal structure of LC3-PE with ATG4/RavZ-mediated deconjugation. Using a combination of molecular docking and biochemical assays, we found that Gln116, Phe119 and Gly120 of LC3-PE are required for cleavage by both RavZ and ATG4B, whereas Glu117(LC3) is specific to cleavage by RavZ. The molecular ruler mechanism exists in the active site of ATG4B, but not in RavZ. Met63 and Gln64 at the active site of RavZ are involved in accommodating LC3 C-terminal motif. Our findings show that the distinct binding modes of the LC3 C-terminal motif (116-120) with ATG4 and RavZ might determine the specificity of ...Continue Reading

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Citations

Oct 24, 2020·Trends in Microbiology·Ligang MeiAimin Yang
Mar 17, 2021·Phytotherapy Research : PTR·Yijia ZengJilin Sun
Mar 3, 2021·The FEBS Journal·Andrey GrishinMiroslaw Cygler
Aug 16, 2021·Cellular Microbiology·Flávia VianaGunnar N Schroeder

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Methods Mentioned

BETA
cleavage assay
lipidation
PCR
affinity purification
size exclusion chromatography

Software Mentioned

Rosetta Dock
ZDOCK
Xcalibur
MagTran

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