9lvk

Structural highlights

Function

WDR59_HUMAN As a component of the GATOR2 complex, functions as an activator of the amino acid-sensing branch of the mTORC1 signaling pathway (PubMed:23723238, PubMed:25457612, PubMed:27487210, PubMed:35831510, PubMed:36528027, PubMed:36577058). The GATOR2 complex indirectly activates mTORC1 through the inhibition of the GATOR1 subcomplex (PubMed:23723238, PubMed:27487210, PubMed:35831510, PubMed:36528027). GATOR2 probably acts as an E3 ubiquitin-protein ligase toward GATOR1 (PubMed:36528027). In the presence of abundant amino acids, the GATOR2 complex mediates ubiquitination of the NPRL2 core component of the GATOR1 complex, leading to GATOR1 inactivation (PubMed:36528027). In the absence of amino acids, GATOR2 is inhibited, activating the GATOR1 complex (PubMed:25457612, PubMed:27487210).^{[1] [2] [3] [4] [5] [6]}

References

1. ↑ Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA, Grabiner BC, Spear ED, Carter SL, Meyerson M, Sabatini DM. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013 May 31;340(6136):1100-6. doi: 10.1126/science.1232044. PMID:23723238 doi:http://dx.doi.org/10.1126/science.1232044
2. ↑ Parmigiani A, Nourbakhsh A, Ding B, Wang W, Kim YC, Akopiants K, Guan KL, Karin M, Budanov AV. Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep. 2014 Nov 20;9(4):1281-91. doi: 10.1016/j.celrep.2014.10.019. PMID:25457612 doi:http://dx.doi.org/10.1016/j.celrep.2014.10.019
3. ↑ Saxton RA, Chantranupong L, Knockenhauer KE, Schwartz TU, Sabatini DM. Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. Nature. 2016 Aug 11;536(7615):229-33. PMID:27487210 doi:http://dx.doi.org/10.1038/nature19079
4. ↑ Valenstein ML, Rogala KB, Lalgudi PV, Brignole EJ, Gu X, Saxton RA, Chantranupong L, Kolibius J, Quast JP, Sabatini DM. Structure of the nutrient-sensing hub GATOR2. Nature. 2022 Jul;607(7919):610-616. doi: 10.1038/s41586-022-04939-z. Epub 2022, Jul 13. PMID:35831510 doi:http://dx.doi.org/10.1038/s41586-022-04939-z
5. ↑ Jiang C, Dai X, He S, Zhou H, Fang L, Guo J, Liu S, Zhang T, Pan W, Yu H, Fu T, Li D, Inuzuka H, Wang P, Xiao J, Wei W. Ring domains are essential for GATOR2-dependent mTORC1 activation. Mol Cell. 2023 Jan 5;83(1):74-89.e9. PMID:36528027 doi:10.1016/j.molcel.2022.11.021
6. ↑ Zhang Y, Ting CY, Yang S, Reich J, Fru K, Lilly MA. Wdr59 promotes or inhibits TORC1 activity depending on cellular context. Proc Natl Acad Sci U S A. 2023 Jan 3;120(1):e2212330120. PMID:36577058 doi:10.1073/pnas.2212330120