Title : Regulation of calcium/calmodulin-dependent kinase IV by O-GlcNAc modification.
Abstract :
Similar to phosphorylation, GlcNAcylation (the addition of O-GlcNAc to Ser ( Thr ) residues on polypeptides ) is an abundant, dynamic, and inducible post-translational modification
GlcNAcylated proteins are crucial in regulating virtually all cellular processes, including signaling, cell cycle, and transcription
Here we show that calcium/calmodulin-dependent kinase IV ( CaMKIV ) is highly GlcNAcylated in vivo
In addition, we show that upon activation of HEK293 cells, hemagglutinin-tagged CaMKIV GlcNAcylation rapidly decreases, in a manner directly opposing its phosphorylation at Thr-200
Correspondingly, there is an increase in CaMKIV interaction with O-GlcNAcase during CaMKIV activation
Furthermore, we identify at least five sites of GlcNAcylation on CaMKIV
Using site-directed mutagenesis, we determine that the GlcNAcylation sites located in the active site of CaMKIV can modulate its phosphorylation at Thr-200 and its activity toward cAMP-response element-binding transcription factor
Our results strongly indicate that the O-GlcNAc modification participates in the regulation of CaMKIV activation and function, possibly coordinating nutritional signals with the immune and nervous systems
This is the first example of an O-GlcNAc/phosphate cycle involving O-GlcNAc transferase/kinase cross-talk