Abstract
Calcium/calmodulin-dependent kinase II (CaMKII) is best known for its roles in learning and memory, but it also plays a role in cancer and cardiac function. Due to its ability to become autonomous upon autophosphorylation, it is proposed to act as a molecular memory. Overactivity of CaMKII, however, is linked to cancer and heart failure. Finding inhibitors of CaMKII could therefore have important health applications. During a mass spectrometry study, our lab discovered that Nme1, a nucleoside diphosphate kinase, interacts with CaMKII. We determined that this interaction results in CaMKII inhibition. In order to characterize this inhibition, we performed a series of kinase assays to monitor the kinase activity of CaMKII. Nme1 can inhibit the activity of CaMKII in both its naïve and autonomous states, and it inhibits S- and T-type substrates equally well. Conversely, Nme1 was found to enhance the activity of CaMKII at concentrations of 0.5 μM compared to the inhibition observed at concentrations at or above 2 μM. Finally, we also determined that the mechanism underlying inhibition of CaMKII kinase activity does not rely on the phospho-transfer capacity of Nme1. Our discovery therefore offers new leads into investigating the mechanisms by which Nme1 affects several pathophysiological processes.