Differential AMP-activated Protein Kinase (AMPK) Recognition Mechanism of Ca2+/Calmodulin-dependent Protein Kinase Kinase Isoforms.

ABSTRACT

Ca(2+)/calmodulin-dependent protein kinase kinase ß (CaMKKß) is a known activating kinase for AMP-activated protein kinase (AMPK). In vitro, CaMKKß phosphorylates Thr(172) in the AMPKα subunit more efficiently than CaMKKα, with a lower Km (∼2 µm) for AMPK, whereas the CaMKIα phosphorylation efficiencies by both CaMKKs are indistinguishable. Here we found that subdomain VIII of CaMKK is involved in the discrimination of AMPK as a native substrate by measuring the activities of various CaMKKα/CaMKKß chimera mutants. Site-directed mutagenesis analysis revealed that Leu(358) in CaMKKß/Ile(322) in CaMKKα confer, at least in part, a distinct recognition of AMPK but not of CaMKIα.