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ULK complex organization in autophagy by a C-shaped FIP200 N-terminal domain dimer.

Authors
  • Shi, Xiaoshan1
  • Yokom, Adam L1
  • Wang, Chunxin2
  • Young, Lindsey N1
  • Youle, Richard J2
  • Hurley, James H1, 3
  • 1 Department of Molecular and Cell Biology and California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA.
  • 2 Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
  • 3 Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA.
Type
Published Article
Journal
The Journal of Cell Biology
Publisher
The Rockefeller University Press
Publication Date
Jul 06, 2020
Volume
219
Issue
7
Identifiers
DOI: 10.1083/jcb.201911047
PMID: 32516362
Source
Medline
Language
English
License
Unknown

Abstract

The autophagy-initiating human ULK complex consists of the kinase ULK1/2, FIP200, ATG13, and ATG101. Hydrogen-deuterium exchange mass spectrometry was used to map their mutual interactions. The N-terminal 640 residues (NTD) of FIP200 interact with the C-terminal IDR of ATG13. Mutations in these regions abolish their interaction. Negative stain EM and multiangle light scattering showed that FIP200 is a dimer, while a single molecule each of the other subunits is present. The FIP200NTD is flexible in the absence of ATG13, but in its presence adopts the shape of the letter C ∼20 nm across. The ULK1 EAT domain interacts loosely with the NTD dimer, while the ATG13:ATG101 HORMA dimer does not contact the NTD. Cryo-EM of the NTD dimer revealed a structural similarity to the scaffold domain of TBK1, suggesting an evolutionary similarity between the autophagy-initiating TBK1 kinase and the ULK1 kinase complex. © 2020 Shi et al.

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