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Crystal structures of S6K1 provide insights into the regulation mechanism of S6K1 by the hydrophobic motif.

Wang J, Zhong C, Wang F, Qu F, Ding J
Biochem J 454 39-47 (2013)
Related entries: 4l3j, 4l3l, 4l43, 4l44, 4l45, 4l46

Cited: 12 times
EuropePMC logo PMID: 23731517

Abstract

The activity of S6K1 (p70 ribosomal protein subunit 6 kinase 1) is stimulated by phosphorylation of Thr389 in the hydrophobic motif by mTORC1 (mammalian target of rapamycin complex 1) and phosphorylation of Thr229 in the activation loop by PDK1 (phosphoinositide-dependent kinase 1); however, the order of the two events is still ambiguous. In the present paper we report six crystal structures of the S6K1 kinase domain alone or plus the hydrophobic motif in various forms, in complexes with a highly specific inhibitor. The structural data, together with the biochemical data, reveal in vivo phosphorylation of Thr389 in the absence of Thr229 phosphorylation and demonstrate the importance of two conserved residues, Gln140 and Arg121, in the establishment of a hydrogen-bonding network between the N-lobe (N-terminal lobe) and the hydrophobic motif. Phosphorylation of Thr389 or introduction of a corresponding negatively charged group leads to reinforcement of the network and stabilization of helix αC. Furthermore, comparisons of S6K1 with other AGC (protein kinase A/protein kinase G/protein kinase C) family kinases suggest that the structural and sequence differences in the hydrophobic motif and helix αC account for their divergence in PDK1 dependency. Taken together, the results of the present study indicate that phosphorylation of the hydrophobic motif in S6K1 is independent of, and probably precedes and promotes, phosphorylation of the activation loop.

Reviews citing this publication (4)

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  2. Recent Discoveries on the Role of TOR (Target of Rapamycin) Signaling in Translation in Plants. Schepetilnikov M, Ryabova LA. Plant Physiol 176 1095-1105 (2018)
  3. The structural basis for mTOR function. Baretić D, Williams RL. Semin Cell Dev Biol 36 91-101 (2014)
  4. Peptidylprolyl Isomerases as In Vivo Carriers for Drugs That Target Various Intracellular Entities. Galat A. Biomolecules 7 E72 (2017)

Articles citing this publication (8)

  1. Cross-talk between sirtuin and mammalian target of rapamycin complex 1 (mTORC1) signaling in the regulation of S6 kinase 1 (S6K1) phosphorylation. Hong S, Zhao B, Lombard DB, Fingar DC, Inoki K. J Biol Chem 289 13132-13141 (2014)
  2. A small-molecule mimic of a peptide docking motif inhibits the protein kinase PDK1. Rettenmaier TJ, Sadowsky JD, Thomsen ND, Chen SC, Doak AK, Arkin MR, Wells JA. Proc Natl Acad Sci U S A 111 18590-18595 (2014)
  3. Inhibiting CARD11 translation during BCR activation by targeting the eIF4A RNA helicase. Steinhardt JJ, Peroutka RJ, Mazan-Mamczarz K, Chen Q, Houng S, Robles C, Barth RN, DuBose J, Bruns B, Tesoriero R, Stein D, Fang R, Hanna N, Pasley J, Rodriguez C, Kligman MD, Bradley M, Rabin J, Shackelford S, Dai B, Landon AL, Scalea T, Livak F, Gartenhaus RB. Blood 124 3758-3767 (2014)
  4. Revealing Different Roles of the mTOR-Targets S6K1 and S6K2 in Breast Cancer by Expression Profiling and Structural Analysis. Karlsson E, Magić I, Bostner J, Dyrager C, Lysholm F, Hallbeck AL, Stål O, Lundström P. PLoS One 10 e0145013 (2015)
  5. Nectandrin B-mediated activation of the AMPK pathway prevents cellular senescence in human diploid fibroblasts by reducing intracellular ROS levels. Jang HJ, Yang KE, Oh WK, Lee SI, Hwang IH, Ban KT, Yoo HS, Choi JS, Yeo EJ, Jang IS. Aging (Albany NY) 11 3731-3749 (2019)
  6. Development of organometallic S6K1 inhibitors. Qin J, Rajaratnam R, Feng L, Salami J, Barber-Rotenberg JS, Domsic J, Reyes-Uribe P, Liu H, Dang W, Berger SL, Villanueva J, Meggers E, Marmorstein R. J Med Chem 58 305-314 (2015)
  7. Crystal structures of the S6K1 kinase domain in complexes with inhibitors. Niwa H, Mikuni J, Sasaki S, Tomabechi Y, Honda K, Ikeda M, Ohsawa N, Wakiyama M, Handa N, Shirouzu M, Honma T, Tanaka A, Yokoyama S. J Struct Funct Genomics 15 153-164 (2014)
  8. Discovery of novel S6K1 inhibitors by an ensemble-based virtual screening method and molecular dynamics simulation. Zhang H, Zhang HR, Zhang J, Hu ML, Ren L, Luo QQ, Qi HZ. J Mol Model 29 102 (2023)


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