Dysbindin structural homologue CK1BP is an isoform-selective binding partner of human casein kinase-1

Casein kinase-1 is a family of ubiquitous eukaryotic protein kinases that frequently function in tandem with the ubiquitin modification system to modulate protein turnover and trafficking. In Alzheimer's disease, these enzymes colocalize with ubiquitinated lesions, including neurofibrillary tangles and granulovacuolar degeneration bodies, suggesting they also play a role in disease pathogenesis. To identify binding partners that potentially regulate or recruit these enzymes toward disease lesions, a Sosrecruitment yeast two-hybrid screen was performed with human Cki delta (the casein kinase-1 isoforrn most closely linked to granulovacuolar degeneration bodies) and a human brain cDNA library. All interacting clones contained a single open reading frame termed casein kinase-1 binding protein (CK1BP). On the basis of sequence alignments, CK1BP was a structural homologue of the acidic domain of dysbindin, a component of the dystrophin-associated protein complex and the biogenesis of lysosome-related organelles complex-1. CK1BP interacted with full-length Cki delta, the isolated Cki delta catalytic domain, Ckiy2, -gamma 3, and -is an element of in the yeast two-hybrid system, and bound Cki delta and -is an element of in pulldown assays but did not interact with Cki alpha. Interaction with the Cki delta catalytic domain led to concentration-dependent inhibition of protein kinase activity in the presence of protein substrates tau and alpha-synuclein. Although intact dysbindin did not bind any CK1 isoform, deletion of its coiled-coil domain yielded a protein fragment that behaved much like CKIBP in two-hybrid screens. These data suggest that the acidic domain of dysbindin and its paralogs in humans may function to recruit casein kinase-1 isoforms to protein complexes involved in multiple biological functions.