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HPK1 citron homology domain regulates phosphorylation of SLP76 and modulates kinase domain interaction dynamics

Author

Listed:
  • Avantika S. Chitre

    (1 DNA Way)

  • Ping Wu

    (1 DNA Way)

  • Benjamin T. Walters

    (1 DNA Way)

  • Xiangdan Wang

    (1 DNA Way)

  • Alexandre Bouyssou

    (1 DNA Way)

  • Xiangnan Du

    (1 DNA Way)

  • Isabelle Lehoux

    (1 DNA Way
    333 Lakeside Drive)

  • Rina Fong

    (1 DNA Way)

  • Alisa Arata

    (1 DNA Way)

  • Joyce Chan

    (1 DNA Way)

  • Die Wang

    (1 DNA Way)

  • Yvonne Franke

    (1 DNA Way)

  • Jane L. Grogan

    (1 DNA Way
    1400 Sierra Point Parkway)

  • Ira Mellman

    (1 DNA Way)

  • Laetitia Comps-Agrar

    (1 DNA Way)

  • Weiru Wang

    (1 DNA Way
    151 Oyster Point Boulevard)

Abstract

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell receptor signaling and as such is an attractive target for cancer immunotherapy. Although the role of the HPK1 kinase domain (KD) has been extensively characterized, the function of its citron homology domain (CHD) remains elusive. Through a combination of structural, biochemical, and mechanistic studies, we characterize the structure-function of CHD in relationship to KD. Crystallography and hydrogen-deuterium exchange mass spectrometry reveal that CHD adopts a seven-bladed β-propellor fold that binds to KD. Mutagenesis associated with binding and functional studies show a direct correlation between domain-domain interaction and negative regulation of kinase activity. We further demonstrate that the CHD provides stability to HPK1 protein in cells as well as contributes to the docking of its substrate SLP76. Altogether, this study highlights the importance of the CHD in the direct and indirect regulation of HPK1 function.

Suggested Citation

  • Avantika S. Chitre & Ping Wu & Benjamin T. Walters & Xiangdan Wang & Alexandre Bouyssou & Xiangnan Du & Isabelle Lehoux & Rina Fong & Alisa Arata & Joyce Chan & Die Wang & Yvonne Franke & Jane L. Grog, 2024. "HPK1 citron homology domain regulates phosphorylation of SLP76 and modulates kinase domain interaction dynamics," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48014-9
    DOI: 10.1038/s41467-024-48014-9
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    References listed on IDEAS

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