title: Structural Basis of Ribosomal S6 Kinase 1 (RSK1) Inhibition by S100B Protein: MODULATION OF THE EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) SIGNALING CASCADE IN A CALCIUM-DEPENDENT WAY.
abstract: Mitogen-activated protein kinases (MAPK) promote MAPK-activated protein kinase activation. In the MAPK pathway responsible for cell growth, ERK2 initiates the first phosphorylation event on RSK1, which is inhibited by Ca(2+)-binding S100 proteins in malignant melanomas. Here, we present a detailed in vitro biochemical and structural characterization of the S100B-RSK1 interaction. The Ca(2+)-dependent binding of S100B to the calcium/calmodulin-dependent protein kinase (CaMK)-type domain of RSK1 is reminiscent of the better known binding of calmodulin to CaMKII. Although S100B-RSK1 and the calmodulin-CAMKII system are clearly distinct functionally, they demonstrate how unrelated intracellular Ca(2+)-binding proteins could influence the activity of the CaMK domain-containing protein kinases. Our crystallographic, small angle x-ray scattering, and NMR analysis revealed that S100B forms a "fuzzy" complex with RSK1 peptide ligands. Based on fast-kinetics experiments, we conclude that the binding involves both conformation selection and induced fit steps. Knowledge of the structural basis of this interaction could facilitate therapeutic targeting of melanomas.
authors.affiliation: From the Department of Biochemistry.
authors.forename: Gergő
authors.initials: G
authors.lastname: Gógl
authors.affiliation: the "Momentum" Protein Interaction Group, Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary, and.
authors.forename: Anita
authors.initials: A
authors.lastname: Alexa
authors.affiliation: From the Department of Biochemistry.
authors.forename: Bence
authors.initials: B
authors.lastname: Kiss
authors.affiliation: the Department of Chemistry and Molecular Biology, University of Gothenburg, 40530 Gothenburg, Sweden.
authors.forename: Gergely
authors.initials: G
authors.lastname: Katona
authors.affiliation: ELTE-MTA "Momentum" Motor Enzymology Research Group, Department of Biochemistry, and.
authors.forename: Mihály
authors.initials: M
authors.lastname: Kovács
authors.affiliation: Institute of Chemistry Eötvös Loránd University, 1117 Budapest, Hungary.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bodor
authors.affiliation: the "Momentum" Protein Interaction Group, Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary, and remenyi.attila@ttk.mta.hu.
authors.forename: Attila
authors.initials: A
authors.lastname: Reményi
authors.affiliation: From the Department of Biochemistry, nyitray@elte.hu.
authors.forename: László
authors.identifier: http://orcid.org/0000-0003-4717-5994
authors.initials: L
authors.lastname: Nyitray
mesh_terms: D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005454:Fluorescence Polarization; D007700:Kinetics; D020935:MAP Kinase Signaling System; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit / Q000737:chemistry / Q000378:metabolism*; D012996:Solutions; D013329:Structure-Activity Relationship; D014364:Tryptophan / Q000378:metabolism
chemical_list: D064568:S100 Calcium Binding Protein beta Subunit; D012996:Solutions; D014364:Tryptophan; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium
keywords: RSK; S100 proteins; calcium; crystal structure; extracellular-signal-regulated kinase (ERK); kinetics; melanoma; mitogen-activated protein kinase (MAPK); nuclear magnetic resonance (NMR); small-angle X-ray scattering (SAXS)