Structural mechanisms of allostery and autoinhibition in JNK family kinases

John D. Laughlin, Jerome C. Nwachukwu, Mariana Figuera-Losada, Lisa Cherry, Kendall W. Nettles, Philip V. Lograsso

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

c-Jun N-terminal (JNK) family kinases have a common peptide-docking site used by upstream activating kinases, substrates, scaffold proteins, and phosphatases, where the ensemble of bound proteins determines signaling output. Although there are many JNK structures, little is known about mechanisms of allosteric regulation between the catalytic and peptide-binding sites, and the activation loop, whose phosphorylation is required for catalytic activity. Here, we compare three structures of unliganded JNK3 bound to different peptides. These were compared as a class to structures that differ in binding of peptide, small molecule ligand, or conformation of the kinase activation loop. Peptide binding induced an inhibitory interlobe conformer that was reversed by alterations in the activation loop. Structure class analysis revealed the subtle structural mechanisms for allosteric signaling between the peptide-binding site and activation loop. Biochemical data from isothermal calorimetry, fluorescence energy transfer, and enzyme inhibition demonstrated affinity differences among the three peptides that were consistent with structural observations.

Original languageEnglish (US)
Pages (from-to)2174-2184
Number of pages11
JournalStructure
Volume20
Issue number12
DOIs
StatePublished - Dec 5 2012
Externally publishedYes

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MAP Kinase Kinase 4
Peptides
Phosphotransferases
Binding Sites
Allosteric Regulation
Calorimetry
Phosphoprotein Phosphatases
Energy Transfer
Fluorescence
Phosphorylation
Ligands
Enzymes

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Laughlin, J. D., Nwachukwu, J. C., Figuera-Losada, M., Cherry, L., Nettles, K. W., & Lograsso, P. V. (2012). Structural mechanisms of allostery and autoinhibition in JNK family kinases. Structure, 20(12), 2174-2184. https://doi.org/10.1016/j.str.2012.09.021

Structural mechanisms of allostery and autoinhibition in JNK family kinases. / Laughlin, John D.; Nwachukwu, Jerome C.; Figuera-Losada, Mariana; Cherry, Lisa; Nettles, Kendall W.; Lograsso, Philip V.

In: Structure, Vol. 20, No. 12, 05.12.2012, p. 2174-2184.

Research output: Contribution to journalArticle

Laughlin, JD, Nwachukwu, JC, Figuera-Losada, M, Cherry, L, Nettles, KW & Lograsso, PV 2012, 'Structural mechanisms of allostery and autoinhibition in JNK family kinases', Structure, vol. 20, no. 12, pp. 2174-2184. https://doi.org/10.1016/j.str.2012.09.021
Laughlin JD, Nwachukwu JC, Figuera-Losada M, Cherry L, Nettles KW, Lograsso PV. Structural mechanisms of allostery and autoinhibition in JNK family kinases. Structure. 2012 Dec 5;20(12):2174-2184. https://doi.org/10.1016/j.str.2012.09.021
Laughlin, John D. ; Nwachukwu, Jerome C. ; Figuera-Losada, Mariana ; Cherry, Lisa ; Nettles, Kendall W. ; Lograsso, Philip V. / Structural mechanisms of allostery and autoinhibition in JNK family kinases. In: Structure. 2012 ; Vol. 20, No. 12. pp. 2174-2184.
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