| 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]
Publication Abstract from PubMed
Autophagy is a bulk degradation pathway that removes cytosolic materials to maintain cellular homeostasis. The autophagy-related gene 13 (Atg13) and microtubule associate protein 1 light chain 3 (LC3) proteins are required for autophagosome formation. We demonstrate that each of the human LC3 isoforms (LC3A, LC3B, and LC3C) interacts with Atg13 via the LC3 interacting region (LIR) of Atg13. Using X-ray crystallography, we solved the macromolecular structures of LC3A and LC3C, along with the complex structures of the LC3 isoforms with the Atg13 LIR. Together, our structural and binding analyses reveal that the side-chain of Lys49 of LC3 acts as a gatekeeper to regulate binding of the LIR. We verified this observation by mutation of Lys49 in LC3A, which significantly reduces LC3A positive puncta formation in cultured cells. Our results suggest that specific affinity of the LC3 isoforms to the Atg13 LIR is required for proper autophagosome formation.
Structural Basis of the Autophagy-Related LC3/Atg13 LIR Complex: Recognition and Interaction Mechanism.,Suzuki H, Tabata K, Morita E, Kawasaki M, Kato R, Dobson RC, Yoshimori T, Wakatsuki S Structure. 2013 Nov 25. pii: S0969-2126(13)00401-2. doi:, 10.1016/j.str.2013.09.023. PMID:24290141[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Suzuki H, Tabata K, Morita E, Kawasaki M, Kato R, Dobson RC, Yoshimori T, Wakatsuki S. Structural Basis of the Autophagy-Related LC3/Atg13 LIR Complex: Recognition and Interaction Mechanism. Structure. 2013 Nov 25. pii: S0969-2126(13)00401-2. doi:, 10.1016/j.str.2013.09.023. PMID:24290141 doi:http://dx.doi.org/10.1016/j.str.2013.09.023
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