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Local destabilization, rigid body, and fuzzy docking facilitate the phosphorylation of the transcription factor Ets-1 by the mitogen-activated protein kinase ERK2
- Source :
- Proceedings of the National Academy of Sciences of the United States of America. 114(31)
- Publication Year :
- 2017
-
Abstract
- Mitogen-activated protein (MAP) kinase substrates are believed to require consensus docking motifs (D-site, F-site) to engage and facilitate efficient site-specific phosphorylation at specific serine/threonine-proline sequences by their cognate kinases. In contrast to other MAP kinase substrates, the transcription factor Ets-1 has no canonical docking motifs, yet it is efficiently phosphorylated by the MAP kinase ERK2 at a consensus threonine site (T38). Using NMR methodology, we demonstrate that this phosphorylation is enabled by a unique bipartite mode of ERK2 engagement by Ets-1 and involves two suboptimal noncanonical docking interactions instead of a single canonical docking motif. The N terminus of Ets-1 interacts with a part of the ERK2 D-recruitment site that normally accommodates the hydrophobic sidechains of a canonical D-site, retaining a significant degree of disorder in its ERK2-bound state. In contrast, the C-terminal region of Ets-1, including its Pointed (PNT) domain, engages in a largely rigid body interaction with a section of the ERK2 F-recruitment site through a binding mode that deviates significantly from that of a canonical F-site. This latter interaction is notable for the destabilization of a flexible helix that bridges the phospho-acceptor site to the rigid PNT domain. These two spatially distinct, individually weak docking interactions facilitate the highly specific recognition of ERK2 by Ets-1, and enable the optimal localization of its dynamic phospho-acceptor T38 at the kinase active site to enable efficient phosphorylation.
- Subjects :
- 0301 basic medicine
MAP Kinase Signaling System
Protein Conformation
Plasma protein binding
Catalysis
Proto-Oncogene Protein c-ets-1
03 medical and health sciences
Protein structure
Humans
Binding site
Phosphorylation
Transcription factor
Nuclear Magnetic Resonance, Biomolecular
Mitogen-Activated Protein Kinase 1
Multidisciplinary
Binding Sites
030102 biochemistry & molecular biology
biology
Kinase
Phosphoproteins
030104 developmental biology
Biochemistry
PNAS Plus
Docking (molecular)
Mitogen-activated protein kinase
Biophysics
biology.protein
Apoptosis Regulatory Proteins
Protein Binding
Subjects
Details
- ISSN :
- 10916490
- Volume :
- 114
- Issue :
- 31
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....10d4241288e4bb16c349049e149b873c