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

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 st

SUBMITTER: Chitre AS 

PROVIDER: S-EPMC11066036 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature