Journal article
Mechanism of activation of protein kinase JAK2 by the growth hormone receptor
AJ Brooks, W Dai, ML O'Mara, D Abankwa, Y Chhabra, RA Pelekanos, O Gardon, KA Tunny, KM Blucher, CJ Morton, MW Parker, E Sierecki, Y Gambin, GA Gomez, K Alexandrov, IA Wilson, M Doxastakis, AE Mark, MJ Waters
Science | Published : 2014
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 mov..
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Awarded by National Science Foundation
Funding Acknowledgements
This work was supported by grants from the National Health and Medical Research Council of Australia (511120, 1002893, and 102082) and the Australian Research Council to M.J.W., A.J.B, A.E.M., and M.W.P. Infrastructure funding from the Victorian Government to St Vincent's Institute is gratefully acknowledged. W.D. and M.D. acknowledge financial support by the NSF (USA) Chemical, Bioengineering, Environmental, and Transport Systems Division (grant number 1067356) and central processing unit time by the University of Houston Research Computing Center. G.A.G. acknowledges financial support by the Kids Cancer Project of the Oncology Research Foundation. We thank W.A. Johnston for optimizing the Leishmania-based cell-free lysate expression system used in the single-molecule and Alpha screen interaction studies. Confocal imaging was performed at the IMB/ACRF Cancer Biology Imaging Facility, established with the support of the Australian Cancer Research Foundation.