Mechanism of activation of protein kinase JAK2 by the growth hormone receptor

Brooks, Andrew J., Dai, Wei, O’Mara, Megan L., Abankwa, Daniel, Chhabra, Yash, Pelekanos, Rebecca A., Gardon, Olivier, Tunny, Kathryn A., Blucher, Kristopher M., Morton, Craig J., Parker, Michael W., Sierecki, Emma, Gambin, Yann, Gomez, Guillermo A., Alexandrov, Kirill, Wilson, Ian A., Doxastakis, Manolis, Mark, Alan E. and Waters, Michael J. (2014) Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science, 344 6185: 1249783.1-1249783.12. doi:10.1126/science.1249783

Author Brooks, Andrew J.
Dai, Wei
O’Mara, Megan L.
Abankwa, Daniel
Chhabra, Yash
Pelekanos, Rebecca A.
Gardon, Olivier
Tunny, Kathryn A.
Blucher, Kristopher M.
Morton, Craig J.
Parker, Michael W.
Sierecki, Emma
Gambin, Yann
Gomez, Guillermo A.
Alexandrov, Kirill
Wilson, Ian A.
Doxastakis, Manolis
Mark, Alan E.
Waters, Michael J.
Title Mechanism of activation of protein kinase JAK2 by the growth hormone receptor
Journal name Science   Check publisher's open access policy
ISSN 0036-8075
Publication date 2014-05-16
Year available 2014
Sub-type Article (original research)
DOI 10.1126/science.1249783
Open Access Status Not yet assessed
Volume 344
Issue 6185
Start page 1249783.1
End page 1249783.12
Total pages 12
Place of publication Washington, DC, United States
Publisher American Association for the Advancement of Science
Language eng
Abstract Signaling from JAK (Janus kinase) protein kinases to STAT (signal transducers and activators of transcription) transcription factors is key to many aspects of biology and medicine, yet the mechanism by which cytokine receptors initiate signaling is enigmatic. We present a complete mechanistic model for activation of receptor-bound JAK2, based on an archetypal cytokine receptor, the growth hormone receptor. For this, we used fluorescence resonance energy transfer to monitor positioning of the JAK2 binding motif in the receptor dimer, substitution of the receptor extracellular domains with Jun zippers to control the position of its transmembrane (TM) helices, atomistic modeling of TM helix movements, and docking of the crystal structures of the JAK2 kinase and its inhibitory pseudokinase domain with an opposing kinase-pseudokinase domain pair. Activation of the receptor dimer induced a separation of its JAK2 binding motifs, driven by a ligand-induced transition from a parallel TM helix pair to a left-handed crossover arrangement. This separation leads to removal of the pseudokinase domain from the kinase domain of the partner JAK2 and pairing of the two kinase domains, facilitating trans-activation. This model may well generalize to other class I cytokine receptors.
Keyword Multidisciplinary Sciences
Science & Technology - Other Topics
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID 511120
Institutional Status UQ
Additional Notes Article # 1249783

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 121 times in Thomson Reuters Web of Science Article | Citations
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Created: Wed, 21 May 2014, 01:11:17 EST by Dr Megan O'mara on behalf of School of Chemistry & Molecular Biosciences