5xv4
Crystal structure of ATG101-ATG13HORMA
Structural highlights
FunctionATG13_HUMAN Autophagy factor required for autophagosome formation and mitophagy. Target of the TOR kinase signaling pathway that regulates autophagy through the control of the phosphorylation status of ATG13 and ULK1, and the regulation of the ATG13-ULK1-RB1CC1 complex. Through its regulation of ULK1 activity, plays a role in the regulation of the kinase activity of mTORC1 and cell proliferation.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedThe 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-ATG13(HORMA) complex is responsible for the binding of the PtdIns3K complex. This region adopts a beta-strand conformation in free ATG101, but either an alpha-helix or random coil in our ATG101-ATG13(HORMA) 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; HsATG13(HORMA): 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; ScAtg13(HORMA): HORMA domain of Atg13 from Sccharomyces cerevisiae; SEC-SAXS: size-exclusion chromatography with small-angle X-ray scattering; SpAtg13(HORMA): 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. The C-terminal region of ATG101 bridges ULK1 and PtdIns3K complex in autophagy initiation.,Kim BW, Jin Y, Kim J, Kim JH, Jung J, Kang S, Kim IY, Kim J, Cheong H, Song HK Autophagy. 2018;14(12):2104-2116. doi: 10.1080/15548627.2018.1504716. Epub 2018, Aug 16. PMID:30081750[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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