Structural basis for membrane recruitment of ATG16L1 by WIPI2 in autophagy

eLife

Erika LF Holzbaur¹  Julia F Riley¹  C Alexander Boecker¹  Xuefeng Ren²  Thomas G Flower²  Cosmo Z Buffalo²  Lisa M Strong³  James H Hurley³  Chunmei Chang³  Andrea KH Stavoe⁴ 

[1] Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, United States;Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, United States;Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States;California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States;Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States;California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, United States;Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, United States;Department of Neurobiology and Anatomy, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, United States;

关键词: autophagy;    mitophagy;    parkinson's disease;    x-ray crystallography;    vesicle reconstitution;    LC3;    Human;   

DOI  :  10.7554/eLife.70372

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY