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

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. Grogan, Ira Mellman (), Laetitia Comps-Agrar () and Weiru Wang ()
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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
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
Ira Mellman: 1 DNA Way
Laetitia Comps-Agrar: 1 DNA Way
Weiru Wang: 1 DNA Way

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48014-9

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