2.50
Hdl Handle:
http://hdl.handle.net/10033/346199
Title:
Extracellular-regulated kinase 2 is activated by the enhancement of hinge flexibility.
Authors:
Sours, Kevin M; Xiao, Yao; Ahn, Natalie G
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.
Affiliation:
Helmholtz Institute for Pharmaceutical Research, Saarland University, Saarbrücken, Germany.
Citation:
Extracellular-regulated kinase 2 is activated by the enhancement of hinge flexibility. 2014, 426 (9):1925-35 J. Mol. Biol.
Journal:
Journal of molecular biology
Issue Date:
1-May-2014
URI:
http://hdl.handle.net/10033/346199
DOI:
10.1016/j.jmb.2014.02.011
PubMed ID:
24534729
Type:
Article
Language:
en
ISSN:
1089-8638
Appears in Collections:
publications of the department of microbial natural substances ([HIPS]MINS)

Full metadata record

DC FieldValue Language
dc.contributor.authorSours, Kevin Men
dc.contributor.authorXiao, Yaoen
dc.contributor.authorAhn, Natalie Gen
dc.date.accessioned2015-03-05T10:54:39Zen
dc.date.available2015-03-05T10:54:39Zen
dc.date.issued2014-05-01en
dc.identifier.citationExtracellular-regulated kinase 2 is activated by the enhancement of hinge flexibility. 2014, 426 (9):1925-35 J. Mol. Biol.en
dc.identifier.issn1089-8638en
dc.identifier.pmid24534729en
dc.identifier.doi10.1016/j.jmb.2014.02.011en
dc.identifier.urihttp://hdl.handle.net/10033/346199en
dc.description.abstractProtein 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.en
dc.language.isoenen
dc.subject.meshAnimalsen
dc.subject.meshDNA Mutational Analysisen
dc.subject.meshMass Spectrometryen
dc.subject.meshMitogen-Activated Protein Kinase 1en
dc.subject.meshModels, Biologicalen
dc.subject.meshModels, Molecularen
dc.subject.meshMutant Proteinsen
dc.subject.meshPhosphorylationen
dc.subject.meshProtein Bindingen
dc.subject.meshProtein Conformationen
dc.subject.meshProtein Processing, Post-Translationalen
dc.subject.meshRatsen
dc.titleExtracellular-regulated kinase 2 is activated by the enhancement of hinge flexibility.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Institute for Pharmaceutical Research, Saarland University, Saarbrücken, Germany.en
dc.identifier.journalJournal of molecular biologyen
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