期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 11, 页码 3409-3414出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1419528112
关键词
NMR; mitogen-activated protein kinase; intrinsically disordered protein; signaling; c-Jun N-terminal kinase
资金
- French Infrastructure for Integrated Structural Biology [ANR-10-INSB-05-02]
- Grenoble Alliance for Integrated Structural and Cell Biology within the Grenoble Partnership for Structural Biology [ANR-10-LABX-49-01]
- French Agence Nationale de la Recherche (ANR) through ANR Jeunes Chercheuses et Jeunes Chercheurs ProteinDisorder
- ANR MALZ TAUSTRUCT
- ANR Complex-Dynamics
- European Commission [264257]
Signaling specificity in the mitogen-activated protein kinase (MAPK) pathways is controlled by disordered domains of the MAPK kinases (MKKs) that specifically bind to their cognate MAPKs via linear docking motifs. MKK7 activates the c-Jun N-terminal kinase (JNK) pathway and is the only MKK containing three motifs within its regulatory domain. Here, we characterize the conformational behavior and interaction mechanism of the MKK7 regulatory domain. Using NMR spectroscopy, we develop an atomic resolution ensemble description of MKK7, revealing highly diverse intrinsic conformational propensities of the three docking sites, suggesting that prerecognition sampling of the bound-state conformation is not prerequisite for binding. Although the different sites exhibit similar affinities for JNK1, interaction kinetics differ considerably. Importantly, we determine the crystal structure of JNK1 in complex with the second docking site of MKK7, revealing two different binding modes of the docking motif correlating with observations from NMR exchange spectroscopy. Our results provide unique insight into how signaling specificity is regulated by linear motifs and, in general, into the role of conformational disorder in MAPK signaling.
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