Extracellular-regulated kinase 2 is activated by the enhancement of hinge flexibility.
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Issue Date
2014-05-01
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Show full item recordAbstract
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.Citation
Extracellular-regulated kinase 2 is activated by the enhancement of hinge flexibility. 2014, 426 (9):1925-35 J. Mol. Biol.Affiliation
Helmholtz Institute for Pharmaceutical Research, Saarland University, Saarbrücken, Germany.Journal
Journal of molecular biologyPubMed ID
24534729Type
ArticleLanguage
enISSN
1089-8638ae974a485f413a2113503eed53cd6c53
10.1016/j.jmb.2014.02.011
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