Structural basis for membrane recruitment of ATG16L1 by WIPI2 in autophagy

Year: 2021

Type: article

Abstract: 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.

Source: eLife

DOI: 10.7554/elife.70372

Authors: 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

Institutions: QB3, Aligning Science Across Parkinson's, University of California, Berkeley, University of Pennsylvania, The University of Texas Health Science Center at Houston

Language: English

Topic: Autophagy in Disease and Therapy

Subfield: Epidemiology

Field: Medicine

Domain: Health Sciences

Open Access status: gold

Estimated APC paid: $2,500

Funders: U.S. Department of Energy, Michael J. Fox Foundation for Parkinson's Research, Deutsche Forschungsgemeinschaft, National Institutes of Health, Office of Science, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, Basic Energy Sciences, Biological and Environmental Research, SLAC National Accelerator Laboratory

OpenAlex ID: W3196608509