Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 14, Pages 5486-5491Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1220306110
Keywords
protein crystallography; protein degradation; protein structure; yeast genetics
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Funding
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of General Medical Sciences
- Damon Runyon Cancer Research Fellowship
- Ruth Kirschtein National Research Service Award Fellowship [GM099319]
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Autophagy-related 13 (Atg13) is a key early-acting factor in autophagy and the major locus for nutrient-dependent regulation of autophagy by Tor. The 2.3-angstrom resolution crystal structure of the N-terminal domain of Atg13 reveals a previously unidentified HORMA (Hop1p, Rev1p and Mad2) domain similar to that of the spindle checkpoint protein Mad2. Mad2 has two different stable conformations, O-Mad2 and C-Mad2, and the Atg13 HORMA structure corresponds to the C-Mad2 state. The Atg13 HORMA domain is required for autophagy and for recruitment of the phosphatidylinositol (PI) 3-kinase subunit Atg14 but is not required for Atg1 interaction or Atg13 recruitment to the preautophagosomal structure. The Atg13 HORMA structure reveals a pair of conserved Arg residues that constitute a putative phosphate sensor. One of the Arg residues is in the region corresponding to the safety belt conformational switch of Mad2, suggesting conformational regulation of phosphate binding. These two Arg residues are essential for autophagy, suggesting that the Atg13 HORMA domain could function as a phosphoregulated conformational switch.
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