ArticleJournal of molecular biology2014
Extracellular-regulated kinase 2 is activated by the enhancement of hinge flexibility.
Article in Journal of molecular biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity.Cancer cell · 2019Trial
- Identification of Novel Extracellular-Signal-Regulated Kinase 2 Inhibitors Through Machine Learning-Driven De Novo Design, Molecular Docking, and Free-Energy Perturbation.Pharmaceuticals (Basel, Switzerland) · 2026Article
- ERK Allosteric Activation: The Importance of Two Ordered Phosphorylation Events.Journal of molecular biology · 2025Article
- Navigating the ERK1/2 MAPK Cascade.Biomolecules · 2023Review
- ATP-competitive inhibitors modulate the substrate binding cooperativity of a kinase by altering its conformational entropy.Science advances · 2022Article
- Mapping the conformational energy landscape of Abl kinase using ClyA nanopore tweezers.Nature communications · 2022Article
- Comparison of tyrosine kinase domain properties for the neurotrophin receptors TrkA and TrkB.The Biochemical journal · 2020Article
- Activation Loop Dynamics Are Coupled to Core Motions in Extracellular Signal-Regulated Kinase-2.Biochemistry · 2020Article
- Kinase Activation by Small Conformational Changes.Journal of chemical information and modeling · 2020Article
- Activation loop dynamics are controlled by conformation-selective inhibitors of ERK2.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Specificity of Phosphorylation Responses to Mitogen Activated Protein (MAP) Kinase Pathway Inhibitors in Melanoma Cells.Molecular & cellular proteomics : MCP · 2018Article
- Endogenous, regulatory cysteine sulfenylation of ERK kinases in response to proliferative signals.Free radical biology & medicine · 2017Article
- Gatekeeper Tyrosine Phosphorylation of SYMRK Is Essential for Synchronizing the Epidermal and Cortical Responses in Root Nodule Symbiosis.Plant physiology · 2016Article
- Attenuation of pattern recognition receptor signaling is mediated by a MAP kinase kinase kinase.EMBO reports · 2016Article
- Adaptability of protein structures to enable functional interactions and evolutionary implications.Current opinion in structural biology · 2015Review
- Parallel Allostery by cAMP and PDE Coordinates Activation and Termination Phases in cAMP Signaling.Biophysical journal · 2015Article
- Article
- Dynamics of protein kinases: insights from nuclear magnetic resonance.Accounts of chemical research · 2015Article
- Applications of hydrogen/deuterium exchange MS from 2012 to 2014.Analytical chemistry · 2015Review
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Protein motions underlie conformational and entropic contributions to enzyme catalysis; however, relatively little is known about the ways in which this occurs. Studies of the mitogen-activated protein kinase ERK2 (extracellular-regulated protein kinase 2) by hydrogen-exchange mass spectrometry suggest that activation enhances backbone flexibility at the linker between N- and C-terminal domains while altering nucleotide binding mode. Here, we address the hypothesis that enhanced backbone flexibility within the hinge region facilitates kinase activation. We show that hinge mutations enhancing flexibility promote changes in the nucleotide binding mode consistent with domain movement, without requiring phosphorylation. They also lead to the activation of monophosphorylated ERK2, a form that is normally inactive. The hinge mutations bypass the need for pTyr but not pThr, suggesting that Tyr phosphorylation controls hinge motions. In agreement, monophosphorylation of pTyr enhances both hinge flexibility and nucleotide binding mode, measured by hydrogen-exchange mass spectrometry. Our findings demonstrate that regulated protein motions underlie kinase activation. Our working model is that constraints to domain movement in ERK2 are overcome by phosphorylation at pTyr, which increases hinge dynamics to promote the active conformation of the catalytic site.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.