Structural basis for membrane recruitment of ATG16L1 by WIPI2 in autophagy

Autophagy is a cellular process that degrades cytoplasmic cargo by engulfing it in a double-membrane vesicle, known as the autophagosome, and delivering it to the lysosome. The ATG12–5–16L1 complex is responsible for conjugating members of the ubiquitin-like ATG8 protein family to phosphatidylethano...

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Autores principales:	Lisa M Strong, Chunmei Chang, Julia F Riley, C Alexander Boecker, Thomas G Flower, Cosmo Z Buffalo, Xuefeng Ren, Andrea KH Stavoe, Erika LF Holzbaur, James H Hurley
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	autophagy mitophagy parkinson's disease x-ray crystallography vesicle reconstitution LC3 Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/3680dcace3464a88937af5f1d613cc8d
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spelling	oai:doaj.org-article:3680dcace3464a88937af5f1d613cc8d2021-12-01T10:56:51ZStructural basis for membrane recruitment of ATG16L1 by WIPI2 in autophagy10.7554/eLife.703722050-084Xe70372https://doaj.org/article/3680dcace3464a88937af5f1d613cc8d2021-09-01T00:00:00Zhttps://elifesciences.org/articles/70372https://doaj.org/toc/2050-084XAutophagy is a cellular process that degrades cytoplasmic cargo by engulfing it in a double-membrane vesicle, known as the autophagosome, and delivering it to the lysosome. The ATG12–5–16L1 complex is responsible for conjugating members of the ubiquitin-like ATG8 protein family to phosphatidylethanolamine in the growing autophagosomal membrane, known as the phagophore. ATG12–5–16L1 is recruited to the phagophore by a subset of the phosphatidylinositol 3-phosphate-binding seven-bladedß -propeller WIPI proteins. We determined the crystal structure of WIPI2d in complex with the WIPI2 interacting region (W2IR) of ATG16L1 comprising residues 207–230 at 1.85 Å resolution. The structure shows that the ATG16L1 W2IR adopts an alpha helical conformation and binds in an electropositive and hydrophobic groove between WIPI2 ß-propeller blades 2 and 3. Mutation of residues at the interface reduces or blocks the recruitment of ATG12–5–16 L1 and the conjugation of the ATG8 protein LC3B to synthetic membranes. Interface mutants show a decrease in starvation-induced autophagy. Comparisons across the four human WIPIs suggest that WIPI1 and 2 belong to a W2IR-binding subclass responsible for localizing ATG12–5–16 L1 and driving ATG8 lipidation, whilst WIPI3 and 4 belong to a second W34IR-binding subclass responsible for localizing ATG2, and so directing lipid supply to the nascent phagophore. The structure provides a framework for understanding the regulatory node connecting two central events in autophagy initiation, the action of the autophagic PI 3-kinase complex on the one hand and ATG8 lipidation on the other.Lisa M StrongChunmei ChangJulia F RileyC Alexander BoeckerThomas G FlowerCosmo Z BuffaloXuefeng RenAndrea KH StavoeErika LF HolzbaurJames H HurleyeLife Sciences Publications Ltdarticleautophagymitophagyparkinson's diseasex-ray crystallographyvesicle reconstitutionLC3MedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	autophagy mitophagy parkinson's disease x-ray crystallography vesicle reconstitution LC3 Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	autophagy mitophagy parkinson's disease x-ray crystallography vesicle reconstitution LC3 Medicine R Science Q Biology (General) QH301-705.5 Lisa M Strong Chunmei Chang Julia F Riley C Alexander Boecker Thomas G Flower Cosmo Z Buffalo Xuefeng Ren Andrea KH Stavoe Erika LF Holzbaur James H Hurley Structural basis for membrane recruitment of ATG16L1 by WIPI2 in autophagy
description	Autophagy is a cellular process that degrades cytoplasmic cargo by engulfing it in a double-membrane vesicle, known as the autophagosome, and delivering it to the lysosome. The ATG12–5–16L1 complex is responsible for conjugating members of the ubiquitin-like ATG8 protein family to phosphatidylethanolamine in the growing autophagosomal membrane, known as the phagophore. ATG12–5–16L1 is recruited to the phagophore by a subset of the phosphatidylinositol 3-phosphate-binding seven-bladedß -propeller WIPI proteins. We determined the crystal structure of WIPI2d in complex with the WIPI2 interacting region (W2IR) of ATG16L1 comprising residues 207–230 at 1.85 Å resolution. The structure shows that the ATG16L1 W2IR adopts an alpha helical conformation and binds in an electropositive and hydrophobic groove between WIPI2 ß-propeller blades 2 and 3. Mutation of residues at the interface reduces or blocks the recruitment of ATG12–5–16 L1 and the conjugation of the ATG8 protein LC3B to synthetic membranes. Interface mutants show a decrease in starvation-induced autophagy. Comparisons across the four human WIPIs suggest that WIPI1 and 2 belong to a W2IR-binding subclass responsible for localizing ATG12–5–16 L1 and driving ATG8 lipidation, whilst WIPI3 and 4 belong to a second W34IR-binding subclass responsible for localizing ATG2, and so directing lipid supply to the nascent phagophore. The structure provides a framework for understanding the regulatory node connecting two central events in autophagy initiation, the action of the autophagic PI 3-kinase complex on the one hand and ATG8 lipidation on the other.
format	article
author	Lisa M Strong Chunmei Chang Julia F Riley C Alexander Boecker Thomas G Flower Cosmo Z Buffalo Xuefeng Ren Andrea KH Stavoe Erika LF Holzbaur James H Hurley
author_facet	Lisa M Strong Chunmei Chang Julia F Riley C Alexander Boecker Thomas G Flower Cosmo Z Buffalo Xuefeng Ren Andrea KH Stavoe Erika LF Holzbaur James H Hurley
author_sort	Lisa M Strong
title	Structural basis for membrane recruitment of ATG16L1 by WIPI2 in autophagy
title_short	Structural basis for membrane recruitment of ATG16L1 by WIPI2 in autophagy
title_full	Structural basis for membrane recruitment of ATG16L1 by WIPI2 in autophagy
title_fullStr	Structural basis for membrane recruitment of ATG16L1 by WIPI2 in autophagy
title_full_unstemmed	Structural basis for membrane recruitment of ATG16L1 by WIPI2 in autophagy
title_sort	structural basis for membrane recruitment of atg16l1 by wipi2 in autophagy
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/3680dcace3464a88937af5f1d613cc8d
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_version_	1718405226777542656

Structural basis for membrane recruitment of ATG16L1 by WIPI2 in autophagy

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