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

Gergo Gógl, Anita Alexa, Bence Kiss, Gergely Katona, M. Kovács, A. Bodor, A. Reményi, L. Nyitray

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Mitogen-activated protein kinases (MAPK) promote MAPKactivated protein kinase activation. In the MAPK pathway responsible for cell growth, ERK2 initiates the first phosphorylation event on RSK1, which is inhibited by Ca2+ -binding S100 proteins in malignant melanomas. Here, we present a detailed in vitro biochemical and structural characterization of the S100B-RSK1 interaction. The Ca2+-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 S100BRSK1 and the calmodulin-CAMKII system are clearly distinct functionally, they demonstrate how unrelated intracellular Ca2+ -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.

Original languageEnglish
Pages (from-to)11-27
Number of pages17
JournalJournal of Biological Chemistry
Volume291
Issue number1
DOIs
Publication statusPublished - Jan 1 2016

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Ribosomal Protein S6 Kinases
Extracellular Signal-Regulated MAP Kinases
Modulation
Calcium
Calcium-Calmodulin-Dependent Protein Kinases
Calmodulin
Mitogen-Activated Protein Kinases
Protein Kinases
Melanoma
Carrier Proteins
Proteins
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Phosphorylation
S100 Proteins
Cell growth
Conformations
Chemical activation
Nuclear magnetic resonance
X-Rays
Scattering

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

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abstract = "Mitogen-activated protein kinases (MAPK) promote MAPKactivated protein kinase activation. In the MAPK pathway responsible for cell growth, ERK2 initiates the first phosphorylation event on RSK1, which is inhibited by Ca2+ -binding S100 proteins in malignant melanomas. Here, we present a detailed in vitro biochemical and structural characterization of the S100B-RSK1 interaction. The Ca2+-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 S100BRSK1 and the calmodulin-CAMKII system are clearly distinct functionally, they demonstrate how unrelated intracellular Ca2+ -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.",
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AU - Gógl, Gergo

AU - Alexa, Anita

AU - Kiss, Bence

AU - Katona, Gergely

AU - Kovács, M.

AU - Bodor, A.

AU - Reményi, A.

AU - Nyitray, L.

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N2 - Mitogen-activated protein kinases (MAPK) promote MAPKactivated protein kinase activation. In the MAPK pathway responsible for cell growth, ERK2 initiates the first phosphorylation event on RSK1, which is inhibited by Ca2+ -binding S100 proteins in malignant melanomas. Here, we present a detailed in vitro biochemical and structural characterization of the S100B-RSK1 interaction. The Ca2+-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 S100BRSK1 and the calmodulin-CAMKII system are clearly distinct functionally, they demonstrate how unrelated intracellular Ca2+ -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.

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