Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex
Copyright policy )Structure and activation of the human autophagy-initiating ULK1C:PI3KC3-C1 supercomplex
Abstract The Unc-51-like kinase protein kinase complex (ULK1C) is the most upstream and central player in the initiation of macroautophagy in mammals. Here, we determined the cryo-electron microscopy structure of the human ULK1C core at amino-acid-level resolution. We also determined a moderate-resolution structure of the ULK1C core in complex with another autophagy core complex, the class III phosphatidylinositol 3-OH kinase complex I (PI3KC3-C1). We show that the two complexes coassemble through extensive contacts between the FIP200 scaffold subunit of ULK1C and the VPS15, ATG14 and BECN1 subunits of PI3KC3-C1. The FIP200:ATG13:ULK1 core of ULK1C undergoes a rearrangement from 2:1:1 to 2:2:2 stoichiometry in the presence of PI3KC3-C1. This suggests a structural mechanism for the initiation of autophagy through formation of a ULK1C:PI3KC3-C1 supercomplex and dimerization of ULK1 on the FIP200 scaffold.
- Monash University Australia
- University of Melbourne Australia
- QB3 United States
- University of California, Berkeley United States
- University of California, San Francisco United States
Models, Molecular, Intracellular Signaling Peptides and Proteins (mesh), 34 Chemical Sciences (for-2020), Autophagy-Related Proteins, 11 Medical and Health Sciences (for), Article, 34 Chemical sciences (for-2020), Models, Class III Phosphatidylinositol 3-Kinases (mesh), 31 Biological sciences (for-2020), Protein Binding (mesh), Autophagy, Humans, Autophagy-Related Protein-1 Homolog, Autophagy-Related Proteins (mesh), Cryoelectron Microscopy (mesh), Developmental Biology (science-metrix), 1.1 Normal biological development and functioning (hrcs-rac), Humans (mesh), 31 Biological Sciences (for-2020), Beclin-1 (mesh), 03 Chemical Sciences (for), Cryoelectron Microscopy, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Autophagy (mesh), Autophagy-Related Protein-1 Homolog (mesh), Class III Phosphatidylinositol 3-Kinases, 3101 Biochemistry and Cell Biology (for-2020), 06 Biological Sciences (for), Molecular (mesh), Adaptor Proteins, Vesicular Transport, Vesicular Transport (mesh), 32 Biomedical and clinical sciences (for-2020), Beclin-1, Biophysics (science-metrix), Protein Binding
Models, Molecular, Intracellular Signaling Peptides and Proteins (mesh), 34 Chemical Sciences (for-2020), Autophagy-Related Proteins, 11 Medical and Health Sciences (for), Article, 34 Chemical sciences (for-2020), Models, Class III Phosphatidylinositol 3-Kinases (mesh), 31 Biological sciences (for-2020), Protein Binding (mesh), Autophagy, Humans, Autophagy-Related Protein-1 Homolog, Autophagy-Related Proteins (mesh), Cryoelectron Microscopy (mesh), Developmental Biology (science-metrix), 1.1 Normal biological development and functioning (hrcs-rac), Humans (mesh), 31 Biological Sciences (for-2020), Beclin-1 (mesh), 03 Chemical Sciences (for), Cryoelectron Microscopy, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Autophagy (mesh), Autophagy-Related Protein-1 Homolog (mesh), Class III Phosphatidylinositol 3-Kinases, 3101 Biochemistry and Cell Biology (for-2020), 06 Biological Sciences (for), Molecular (mesh), Adaptor Proteins, Vesicular Transport, Vesicular Transport (mesh), 32 Biomedical and clinical sciences (for-2020), Beclin-1, Biophysics (science-metrix), Protein Binding
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