Deciphering the unique autoregulatory mechanisms and substrate specificity of the understudied DCLK3 kinase linked to neurodegenerative diseases.

ABSTRACT: Protein kinases represent one of the largest and most druggable protein families. Despite considerable progress in their understanding, approximately one-third of human kinases remain poorly characterized, known as the "dark" kinome. Doublecortin-like kinase 3 (DCLK3), a member of this elusive group, has emerged for its involvement in neuroprotection in Huntington's disease and other neurodegenerative disorders. Still, its cellular substrates and regulatory functions remain unknown, hindering progress in therapeutic intervention. Unlike its paralog, DCLK1, whose regulation involves a C-terminal segment docking into the ATP-binding pocket, DCLK3 lacks such a tail, suggesting divergent regulatory mechanisms. Through computational and experimental analyses, we discovered that DCLK3 autophosph

SUBMITTER: Lu JD 

PROVIDER: S-EPMC12509982 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature