Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 38, Pages 31681-31690Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.397570
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Funding
- Japan Society for the Promotion of Science (JSPS) [23687012, 10J01988, 23000015]
- Ministry of Education, Culture, Sports, Science, and Technology (MEXT) [24113725]
- Targeted Proteins Research Program
- Leave a Nest Grant BioGARAGE award
- Grants-in-Aid for Scientific Research [24770182, 10J01988, 24113725, 23687012] Funding Source: KAKEN
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Autophagy is an intracellular degradation system by which cytoplasmic materials are enclosed by an autophagosome and delivered to a lysosome/vacuole. Atg18 plays a critical role in autophagosome formation as a complex with Atg2 and phosphatidylinositol 3-phosphate (PtdIns(3) P). However, little is known about the structure of Atg18 and its recognition mode of Atg2 or PtdIns(3) P. Here, we report the crystal structure of Kluyveromyces marxianus Hsv2, an Atg18 paralog, at 2.6 angstrom resolution. The structure reveals a seven-bladed beta-propeller without circular permutation. Mutational analyses of Atg18 based on the K. marxianus Hsv2 structure suggested that Atg18 has two phosphoinositide-binding sites at blades 5 and 6, whereas the Atg2-binding region is located at blade 2. Point mutations in the loops of blade 2 specifically abrogated autophagy without affecting another Atg18 function, the regulation of vacuolar morphology at the vacuolar membrane. This architecture enables Atg18 to form a complex with Atg2 and PtdIns(3) P in parallel, thereby functioning in the formation of autophagosomes at autophagic membranes.
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