The C-terminal region of ATG101 bridges ULK1 and PtdIns3K complex in autophagy initiation

Byeong Won Kim, Yunjung Jin, Jiyea Kim, Jun Hoe Kim, Juneyoung Jung, Seongman Kang, Ick Young Kim, Joungmok Kim, Heesun Cheong, Hyun Kyu Song

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)


The initiation of macroautophagy/autophagy is tightly regulated by the upstream ULK1 kinase complex, which affects many downstream factors including the PtdIns3K complex. The phosphorylation of the right position at the right time on downstream molecules is governed by proper complex formation. One component of the ULK1 complex, ATG101, known as an accessory protein, is a stabilizer of ATG13 in cells. The WF finger region of ATG101 plays an important role in the recruitment of WIPI1 (WD repeat domain, phosphoinositide interacting protein 1) and ZFYVE1 (zinc finger FYVE-type containing 1). Here, we report that the C-terminal region identified in the structure of the human ATG101-ATG13HORMA complex is responsible for the binding of the PtdIns3K complex. This region adopts a β-strand conformation in free ATG101, but either an α-helix or random coil in our ATG101-ATG13HORMA complex, which protrudes from the core and interacts with other molecules. The C-terminal deletion of ATG101 shows a significant defect in the interaction with PtdIns3K components and subsequently impairs autophagosome formation. This result clearly presents an additional role of ATG101 for bridging the ULK1 and PtdIns3K complexes in the mammalian autophagy process. Abbreviations: ATG: autophagy related; BECN1: beclin 1; GFP: green fluorescent protein; HORMA: Hop1p/Rev7p/MAD2; HsATG13HORMA: HORMA domain of ATG13 from Homo sapiens; KO: knockout; MAD2: mitotic arrest deficient 2 like 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15: phosphoinositide-3-kinase regulatory subunit 4; PtdIns3K: phosphatidylinositol 3-kinase; RB1CC1/FIP200: RB1 inducible coiled-coil 1; SAXS: small-angle X-ray scattering; ScAtg13HORMA: HORMA domain of Atg13 from Sccharomyces cerevisiae; SEC-SAXS: size-exclusion chromatography with small-angle X-ray scattering; SpAtg13HORMA: HORMA domain of Atg13 from Schizosaccharomyces pombe; SQSTM1/p62: sequestosome 1; ULK1: unc51-like autophagy activating kinase 1; UVRAG: UV radiation resistance associated; WIPI1: WD repeat domain: phosphoinositide interacting 1; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1.

Original languageEnglish
Pages (from-to)2104-2116
Number of pages13
Issue number12
Publication statusPublished - 2018 Dec 2

Bibliographical note

Funding Information:
We thank the staff at beamline 5C and 11C, Pohang Accelerator Laboratory, Korea and beamline BL17A and NE3A, Photon Factory, Japan for their help with the X-ray data collection. This work was in part performed under the International Collaborative Research Program of Institute for Protein Research, Osaka University (ICR-17-05). Diffraction data were collected at the Osaka University beamline BL44XU at SPring-8 (Harima, Japan) (Proposal Nos. 2017A6775 and 2017B6775). We also thank the staff at beamline BL10C, Photon Factory, Japan and beamline 4C, Pohang Accelerator Laboratory, Korea for their help with the SAXS data collection. MIA PaCa-2 human pancreatic cancer cell line was kindly provided by Dr. Yun-Hee Kim, National Cancer Center, Korea.

Funding Information:
This work was supported by National Research Foundation of Korea (NRF) grants from the Korean government (NRF-2016R1E1A1A01942623, BRL grant: No. 2015041919, and International Cooperation Program: No. 2015K2A2A6002008 to H.K.S.; NRF-2017R1A2B4011732 to H.C.).

Publisher Copyright:
© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.


  • ATG101
  • ATG13
  • C-terminal region
  • PtdIns3K complex
  • ULK1 complex
  • structure

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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