@article{856c7243a05440bdaae9f5804156555a,
title = "Dynamic control of RSK complexes by phosphoswitch-based regulation",
abstract = "Assembly and disassembly of protein–protein complexes needs to be dynamically controlled and phosphoswitches based on linear motifs are crucial in this process. Extracellular signal–regulated kinase 2 (ERK2) recognizes a linear-binding motif at the C-terminal tail (CTT) of ribosomal S6 kinase 1 (RSK1), leading to phosphorylation and subsequent activation of RSK1. The CTT also contains a classical PDZ domain-binding motif which binds RSK substrates (e.g. MAGI-1). We show that autophosphorylation of the disordered CTT promotes the formation of an intramolecular charge clamp, which efficiently masks critical residues and indirectly hinders ERK binding. Thus, RSK1 CTT operates as an autoregulated phosphoswitch: its phosphorylation at specific sites affects its protein-binding capacity and its conformational dynamics. These biochemical feedbacks, which form the structural basis for the rapid dissociation of ERK2-RSK1 and RSK1-PDZ substrate complexes under sustained epidermal growth factor (EGF) stimulation, were structurally characterized and validated in living cells. Overall, conformational changes induced by phosphorylation in disordered regions of protein kinases, coupled to allosteric events occurring in the kinase domain cores, may provide mechanisms that contribute to the emergence of complex signaling activities. In addition, we show that phosphoswitches based on linear motifs can be functionally classified as ON and OFF protein–protein interaction switches or dimmers, depending on the specific positioning of phosphorylation target sites in relation to functional linear-binding motifs. Moreover, interaction of phosphorylated residues with positively charged residues in disordered regions is likely to be a common mechanism of phosphoregulation. Database: Structural data are available in the PDB database under the accession numbers 5N7D, 5N7F and 5N7G. NMR spectral assignation data are available in the BMRB database under the accession numbers 27213 and 27214.",
keywords = "extracellular signal–regulated kinase, linear-binding motif, mitogen-activated kinases, PDZ domain, protein phosphorylation, signal transduction",
author = "Gerg{\H o} G{\'o}gl and Be{\'a}ta Biri-Kov{\'a}cs and P{\'o}ti, {{\'A}d{\'a}m L.} and Henrietta Vad{\'a}szi and B{\'a}lint Szeder and Andrea Bodor and Gitta Schlosser and Andr{\'a}s {\'A}cs and Lilla Turi{\'a}k and L{\'a}szl{\'o} Buday and Anita Alexa and L{\'a}szl{\'o} Nyitray and Attila Rem{\'e}nyi",
note = "Funding Information: This work was supported by the National Research, Development and Innovation Office (NKFIH) grants: NN114309, K108798 (to AR), K119359 (to LN). The authors thank Gilles Trav{\'e}for the expression vectors of the MAGI-1 PDZ domain and for the critical reading of the manuscript. We also thank Bence Kiss, Arnold Steckel, Kitti Koprivanacz, Karoly Liliom, and Jozsef Kardos for their help in some of the experiments, as well as Gergely Katona for careful reading of the manuscript. This work has been supported by iNEXT project number 653706, funded by the Horizon 2020 program of the European Union. The authors thank the support of the BAG project MX-378 and the beam line scientist at EMBL Hamburg P13/P14 and PSI SLS PXIII. GG and BBK were supported through the New National Excellence Program of the Hungarian Ministry of Human Capacities. GS acknowledges the support of the J{\'a}nos Bolyai Research Scholarship of the Hungarian Academy of Sciences. AR is the recipient of the Momentum Grant from the Hungarian Academy of the Sciences (LP2013-57). We also thank the support of the MedIn-Prot program of the Hungarian Academy of Sciences, the National Development Agency Grant (KMOP-4.2.1/B-10-2011), NVKP_16-1-2016-0037, VEKOP-2.3.3.-15-2016-00011, and FIEK16-1-2016-0005 grants from the National Research, Development and Innovation Office, Hungary. Funding Information: This work was supported by the National Research, Development and Innovation Office (NKFIH) grants: NN114309, K108798 (to AR), K119359 (to LN). The authors thank Gilles Trav? for the expression vectors of the MAGI-1 PDZ domain and for the critical reading of the manuscript. We also thank Bence Kiss, Arnold Steckel, Kitti Koprivanacz, Karoly Liliom, and Jozsef Kardos for their help in some of the experiments, as well as Gergely Katona for careful reading of the manuscript. This work has been supported by iNEXT project number 653706, funded by the Horizon 2020 program of the European Union. The authors thank the support of the BAG project MX-378 and the beam line scientist at EMBL Hamburg P13/P14 and PSI SLS PXIII. GG and BBK were supported through the New National Excellence Program of the Hungarian Ministry of Human Capacities. GS acknowledges the support of the J?nos Bolyai Research Scholarship of the Hungarian Academy of Sciences. AR is the recipient of the Momentum Grant from the Hungarian Academy of the Sciences (LP2013-57). We also thank the support of the MedInProt program of the Hungarian Academy of Sciences, the National Development Agency Grant (KMOP-4.2.1/B-10-2011), NVKP_16-1-2016-0037, VEKOP-2.3.3.-15-2016-00011, and FIEK16-1-2016-0005 grants from the National Research, Development and Innovation Office, Hungary. Publisher Copyright: {\textcopyright} 2017 Federation of European Biochemical Societies Copyright: Copyright 2018 Elsevier B.V., All rights reserved.",
year = "2018",
month = jan,
doi = "10.1111/febs.14311",
language = "English",
volume = "285",
pages = "46--71",
journal = "FEBS Journal",
issn = "1742-464X",
publisher = "Wiley",
number = "1",
}