Journal article
Structure of SgK223 pseudokinase reveals novel mechanisms of homotypic and heterotypic association
O Patel, MDW Griffin, S Panjikar, W Dai, X Ma, H Chan, C Zheng, A Kropp, JM Murphy, RJ Daly, IS Lucet
Nature Communications | NATURE PUBLISHING GROUP | Published : 2017
Abstract
The mammalian pseudokinase SgK223, and its structurally related homologue SgK269, are oncogenic scaffolds that nucleate the assembly of specific signalling complexes and regulate tyrosine kinase signalling. Both SgK223 and SgK269 form homo- and hetero-oligomers, a mechanism that underpins a diversity of signalling outputs. However, mechanistic insights into SgK223 and SgK269 homo- and heterotypic association are lacking. Here we present the crystal structure of SgK223 pseudokinase domain and its adjacent N- and C-terminal helices. The structure reveals how the N- and C-regulatory helices engage in a novel fold to mediate the assembly of a high-affinity dimer. In addition, we identified regul..
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Awarded by State Government of Victoria
Funding Acknowledgements
O.P. and M.D.W.G. were supported by ARC Future Fellowships (FT120100056 and FT140100544, respectively). J.M.M. and R.J.D. were supported by NHMRC Fellowships (1105754 and 1058540, respectively). Additional support was received from the Australian Cancer Research Foundation (to I.S.L., W.D., O.P., A. K. and C.Z.). I.S.L. acknowledges support from the Walter and Eliza Hall Institute of Medical Research. This work was also supported by funds from the Operational Infrastructure Support Program provided by the Victorian Government, Australia and NHMRC IRIISS 9000220, and in part by a Project Grant (1084621) from the NHMRC (to R.J.D.). Crystallization experiments were performed at CSIRO Collaborative Crystallization Centre (www.csiro.au/C3), Melbourne, Australia. We thank MX and SAXS beamline staff at the Australian Synchrotron where diffraction and scattering data were collected. We acknowledge the facilities, scientific and technical assistance of Monash Micro Imaging, Monash University, Victoria, Australia and Mandy Magias for technical assistance.