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| | ==Crystal structure of ATG101-ATG13HORMA== | | ==Crystal structure of ATG101-ATG13HORMA== |
| - | <StructureSection load='5xuy' size='340' side='right' caption='[[5xuy]], [[Resolution|resolution]] 2.20Å' scene=''> | + | <StructureSection load='5xuy' size='340' side='right'caption='[[5xuy]], [[Resolution|resolution]] 2.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5xuy]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XUY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5XUY FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5xuy]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XUY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5XUY FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ATG13, KIAA0652 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), ATG101, C12orf44, PP894 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5xuy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xuy OCA], [http://pdbe.org/5xuy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5xuy RCSB], [http://www.ebi.ac.uk/pdbsum/5xuy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5xuy ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5xuy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xuy OCA], [https://pdbe.org/5xuy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5xuy RCSB], [https://www.ebi.ac.uk/pdbsum/5xuy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5xuy ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ATG13_HUMAN ATG13_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.<ref>PMID:19287211</ref> <ref>PMID:19211835</ref> <ref>PMID:19225151</ref> <ref>PMID:21855797</ref> <ref>PMID:18936157</ref> <ref>PMID:21795849</ref> [[http://www.uniprot.org/uniprot/ATGA1_HUMAN ATGA1_HUMAN]] Autophagy factor required for autophagosome formation. Stabilizes ATG13, protecting it from proteasomal degradation.<ref>PMID:19287211</ref> <ref>PMID:19597335</ref> | + | [https://www.uniprot.org/uniprot/ATG13_HUMAN ATG13_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.<ref>PMID:19287211</ref> <ref>PMID:19211835</ref> <ref>PMID:19225151</ref> <ref>PMID:21855797</ref> <ref>PMID:18936157</ref> <ref>PMID:21795849</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | 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-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.
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| - | 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<ref>PMID:30081750</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 5xuy" style="background-color:#fffaf0;"></div>
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| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Kim, B W]] | + | [[Category: Large Structures]] |
| - | [[Category: Song, H K]] | + | [[Category: Kim B-W]] |
| - | [[Category: Atg101]] | + | [[Category: Song HK]] |
| - | [[Category: Atg13]]
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| - | [[Category: Autophagy]]
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| - | [[Category: Horma]]
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| - | [[Category: Protein binding]]
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| Structural highlights
Function
ATG13_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]
References
- ↑ Mercer CA, Kaliappan A, Dennis PB. A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy. Autophagy. 2009 Jul;5(5):649-62. Epub 2009 Jul 20. PMID:19287211
- ↑ Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, Iemura S, Natsume T, Takehana K, Yamada N, Guan JL, Oshiro N, Mizushima N. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell. 2009 Apr;20(7):1981-91. doi: 10.1091/mbc.E08-12-1248. Epub 2009, Feb 11. PMID:19211835 doi:http://dx.doi.org/10.1091/mbc.E08-12-1248
- ↑ Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, Kundu M, Kim DH. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell. 2009 Apr;20(7):1992-2003. doi: 10.1091/mbc.E08-12-1249. Epub 2009 , Feb 18. PMID:19225151 doi:http://dx.doi.org/10.1091/mbc.E08-12-1249
- ↑ Joo JH, Dorsey FC, Joshi A, Hennessy-Walters KM, Rose KL, McCastlain K, Zhang J, Iyengar R, Jung CH, Suen DF, Steeves MA, Yang CY, Prater SM, Kim DH, Thompson CB, Youle RJ, Ney PA, Cleveland JL, Kundu M. Hsp90-Cdc37 chaperone complex regulates Ulk1- and Atg13-mediated mitophagy. Mol Cell. 2011 Aug 19;43(4):572-85. doi: 10.1016/j.molcel.2011.06.018. PMID:21855797 doi:http://dx.doi.org/10.1016/j.molcel.2011.06.018
- ↑ Chan EY, Longatti A, McKnight NC, Tooze SA. Kinase-inactivated ULK proteins inhibit autophagy via their conserved C-terminal domains using an Atg13-independent mechanism. Mol Cell Biol. 2009 Jan;29(1):157-71. doi: 10.1128/MCB.01082-08. Epub 2008 Oct, 20. PMID:18936157 doi:http://dx.doi.org/10.1128/MCB.01082-08
- ↑ Jung CH, Seo M, Otto NM, Kim DH. ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. Autophagy. 2011 Oct;7(10):1212-21. doi: 10.4161/auto.7.10.16660. Epub 2011 Oct 1. PMID:21795849 doi:http://dx.doi.org/10.4161/auto.7.10.16660
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