Structure of SgK223 pseudokinase reveals novel mechanisms of homotypic and heterotypic association

Onisha Patel (), Michael D. W. Griffin, Santosh Panjikar, Weiwen Dai, Xiuquan Ma, Howard Chan, Celine Zheng, Ashleigh Kropp, James M. Murphy, Roger J. Daly and Isabelle S. Lucet ()
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Onisha Patel: The Walter and Eliza Hall Institute of Medical Research
Michael D. W. Griffin: Bio21 Molecular Science and Biotechnology Institute, University of Melbourne
Santosh Panjikar: Australian Synchrotron
Weiwen Dai: The Walter and Eliza Hall Institute of Medical Research
Xiuquan Ma: Level 1, Building 77, Monash University
Howard Chan: Level 1, Building 77, Monash University
Celine Zheng: The Walter and Eliza Hall Institute of Medical Research
Ashleigh Kropp: The Walter and Eliza Hall Institute of Medical Research
James M. Murphy: The Walter and Eliza Hall Institute of Medical Research
Roger J. Daly: Level 1, Building 77, Monash University
Isabelle S. Lucet: The Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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 regulatory interfaces on the pseudokinase domain required for the self-assembly of large open-ended oligomers. This study highlights the diversity in how the kinase fold mediates non-catalytic functions and provides mechanistic insights into how the assembly of these two oncogenic scaffolds is achieved in order to regulate signalling output.

Date: 2017
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DOI: 10.1038/s41467-017-01279-9

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