7MU2

Crystal Structure of WIPI2 in complex with W2IR of ATG16L1

Summary for 7MU2

• Entry DOI: 10.2210/pdb7mu2/pdb
• Descriptor: WD repeat domain phosphoinositide-interacting protein 2, Autophagy-related protein 16-1 (3 entities in total)
• Functional Keywords: autophagy, wipi2, atg16, lipid binding protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 4
• Total formula weight: 77208.52

Authors

Strong, L.M.,Flower, T.G.,Buffalo, C.Z.,Hurley, J.H. (deposition date: 2021-05-14, release date: 2021-05-26, Last modification date: 2023-10-18)

Primary citation

Strong, L.M.,Chang, C.,Riley, J.F.,Boecker, C.A.,Flower, T.G.,Buffalo, C.Z.,Ren, X.,Stavoe, A.K.,Holzbaur, E.L.,Hurley, J.H.
Structural basis for membrane recruitment of ATG16L1 by WIPI2 in autophagy.
Elife, 10:-, 2021

PubMed 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.

PubMed: 34505572
DOI: 10.7554/eLife.70372

Experimental method

X-RAY DIFFRACTION (1.85 Å)