Molecular basis for receptor tyrosine kinase A-loop tyrosine transphosphorylation

Lingfeng Chen, William M. Marsiglia, Huaibin Chen, Joseph Katigbak, Hediye Erdjument-Bromage, David J. Kemble, Lili Fu, Jinghong Ma, Gongqin Sun, Yingkai Zhang, Guang Liang, Thomas A. Neubert, Xiaokun Li, Nathaniel J. Traaseth, Moosa Mohammadi

Research output: Contribution to journalArticle

Abstract

A long-standing mystery shrouds the mechanism by which catalytically repressed receptor tyrosine kinase domains accomplish transphosphorylation of activation loop (A-loop) tyrosines. Here we show that this reaction proceeds via an asymmetric complex that is thermodynamically disadvantaged because of an electrostatic repulsion between enzyme and substrate kinases. Under physiological conditions, the energetic gain resulting from ligand-induced dimerization of extracellular domains overcomes this opposing clash, stabilizing the A-loop-transphosphorylating dimer. A unique pathogenic fibroblast growth factor receptor gain-of-function mutation promotes formation of the complex responsible for phosphorylation of A-loop tyrosines by eliminating this repulsive force. We show that asymmetric complex formation induces a more phosphorylatable A-loop conformation in the substrate kinase, which in turn promotes the active state of the enzyme kinase. This explains how quantitative differences in the stability of ligand-induced extracellular dimerization promotes formation of the intracellular A-loop-transphosphorylating asymmetric complex to varying extents, thereby modulating intracellular kinase activity and signaling intensity.

Original languageEnglish (US)
Pages (from-to)267-277
Number of pages11
JournalNature Chemical Biology
Volume16
Issue number3
DOIs
StatePublished - Mar 1 2020

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Chen, L., Marsiglia, W. M., Chen, H., Katigbak, J., Erdjument-Bromage, H., Kemble, D. J., Fu, L., Ma, J., Sun, G., Zhang, Y., Liang, G., Neubert, T. A., Li, X., Traaseth, N. J., & Mohammadi, M. (2020). Molecular basis for receptor tyrosine kinase A-loop tyrosine transphosphorylation. Nature Chemical Biology, 16(3), 267-277. https://doi.org/10.1038/s41589-019-0455-7