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

Author

Listed:
  • Onisha Patel

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Michael D. W. Griffin

    (Bio21 Molecular Science and Biotechnology Institute, University of Melbourne)

  • Santosh Panjikar

    (Australian Synchrotron
    Level 1, Building 77, Monash University)

  • Weiwen Dai

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Xiuquan Ma

    (Level 1, Building 77, Monash University
    Monash University)

  • Howard Chan

    (Level 1, Building 77, Monash University
    Monash University)

  • Celine Zheng

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Ashleigh Kropp

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • James M. Murphy

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Roger J. Daly

    (Level 1, Building 77, Monash University
    Monash University)

  • Isabelle S. Lucet

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

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.

Suggested Citation

  • Onisha Patel & Michael D. W. Griffin & Santosh Panjikar & Weiwen Dai & Xiuquan Ma & Howard Chan & Celine Zheng & Ashleigh Kropp & James M. Murphy & Roger J. Daly & Isabelle S. Lucet, 2017. "Structure of SgK223 pseudokinase reveals novel mechanisms of homotypic and heterotypic association," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01279-9
    DOI: 10.1038/s41467-017-01279-9
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    Cited by:

    1. Michael J. Roy & Minglyanna G. Surudoi & Ashleigh Kropp & Jianmei Hou & Weiwen Dai & Joshua M. Hardy & Lung-Yu Liang & Thomas R. Cotton & Bernhard C. Lechtenberg & Toby A. Dite & Xiuquan Ma & Roger J., 2023. "Structural mapping of PEAK pseudokinase interactions identifies 14-3-3 as a molecular switch for PEAK3 signaling," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Hayarpi Torosyan & Michael D. Paul & Antoine Forget & Megan Lo & Devan Diwanji & Krzysztof Pawłowski & Nevan J. Krogan & Natalia Jura & Kliment A. Verba, 2023. "Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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