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Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3

Author

Listed:
  • Hayarpi Torosyan

    (University of California San Francisco
    University of California San Francisco)

  • Michael D. Paul

    (University of California San Francisco)

  • Antoine Forget

    (University of California San Francisco
    University of California San Francisco)

  • Megan Lo

    (University of California San Francisco)

  • Devan Diwanji

    (University of California San Francisco
    University of California San Francisco)

  • Krzysztof Pawłowski

    (University of Texas Southwestern Medical Center
    Warsaw University of Life Sciences)

  • Nevan J. Krogan

    (University of California San Francisco
    University of California San Francisco
    J. David Gladstone Institutes)

  • Natalia Jura

    (University of California San Francisco
    University of California San Francisco
    University of California San Francisco)

  • Kliment A. Verba

    (University of California San Francisco
    University of California San Francisco)

Abstract

PEAK pseudokinases are molecular scaffolds which dimerize to regulate cell migration, morphology, and proliferation, as well as cancer progression. The mechanistic role dimerization plays in PEAK scaffolding remains unclear, as there are no structures of PEAKs in complex with their interactors. Here, we report the cryo-EM structure of dimeric PEAK3 in complex with an endogenous 14-3-3 heterodimer. Our structure reveals an asymmetric binding mode between PEAK3 and 14-3-3 stabilized by one pseudokinase domain and the SHED domain of the PEAK3 dimer. The binding interface contains a canonical phosphosite-dependent primary interaction and a unique secondary interaction not observed in previous structures of 14-3-3/client complexes. Additionally, we show that PKD regulates PEAK3/14-3-3 binding, which when prevented leads to PEAK3 nuclear enrichment and distinct protein-protein interactions. Altogether, our data demonstrate that PEAK3 dimerization forms an unusual secondary interface for 14-3-3 binding, facilitating 14-3-3 regulation of PEAK3 localization and interactome diversity.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38864-0
    DOI: 10.1038/s41467-023-38864-0
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    References listed on IDEAS

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    1. Tobias Karlberg & Peter Hornyak & Ana Filipa Pinto & Stefina Milanova & Mahsa Ebrahimi & Mikael Lindberg & Nikolai Püllen & Axel Nordström & Elinor Löverli & Rémi Caraballo & Emily V. Wong & Katja När, 2018. "14-3-3 proteins activate Pseudomonas exotoxins-S and -T by chaperoning a hydrophobic surface," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    2. 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.
    3. Yong Zheng & Cunjie Zhang & David R. Croucher & Mohamed A. Soliman & Nicole St-Denis & Adrian Pasculescu & Lorne Taylor & Stephen A. Tate & W. Rod Hardy & Karen Colwill & Anna Yue Dai & Rick Bagshaw &, 2013. "Temporal regulation of EGF signalling networks by the scaffold protein Shc1," Nature, Nature, vol. 499(7457), pages 166-171, July.
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    Cited by:

    1. Zhuo Han & Rui Wang & Pengliang Chi & Zihan Zhang & Ling Min & Haizhan Jiao & Guojin Ou & Dan Zhou & Dandan Qin & Chengpeng Xu & Zheng Gao & Qianqian Qi & Jialu Li & Yuechao Lu & Xiang Wang & Jing Che, 2024. "The subcortical maternal complex modulates the cell cycle during early mammalian embryogenesis via 14-3-3," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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