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The KN-93 Molecule Inhibits Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity by Binding to Ca/CaM. | LitMetric

AI Article Synopsis

  • - CaMKII is an important enzyme activated by calcium-bound calmodulin (Ca/CaM), which plays a role in various cellular functions and is a target for disease management.
  • - The commonly used inhibitor KN-93 was believed to bind CaMKII directly, but new research shows it actually binds to Ca/CaM, interfering with CaMKII activation instead.
  • - These findings suggest that the use of KN-93 in experiments requires a reevaluation and highlights the need to consider its effects on other Ca/CaM-dependent processes beyond CaMKII.

Article Abstract

Calcium/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional serine/threonine protein kinase that transmits calcium signals in various cellular processes. CaMKII is activated by calcium-bound calmodulin (Ca/CaM) through a direct binding mechanism involving a regulatory C-terminal α-helix in CaMKII. The Ca/CaM binding triggers transphosphorylation of critical threonine residues proximal to the CaM-binding site leading to the autoactivated state of CaMKII. The demonstration of its critical roles in pathophysiological processes has elevated CaMKII to a key target in the management of numerous diseases. The molecule KN-93 is the most widely used inhibitor for studying the cellular and in vivo functions of CaMKII. It is widely believed that KN-93 binds directly to CaMKII, thus preventing kinase activation by competing with Ca/CaM. Herein, we employed surface plasmon resonance, NMR, and isothermal titration calorimetry to characterize this presumed interaction. Our results revealed that KN-93 binds directly to Ca/CaM and not to CaMKII. This binding would disrupt the ability of Ca/CaM to interact with CaMKII, effectively inhibiting CaMKII activation. Our findings also indicated that KN-93 can specifically compete with a CaMKIIδ-derived peptide for binding to Ca/CaM. As indicated by the surface plasmon resonance and isothermal titration calorimetry data, apparently at least two KN-93 molecules can bind to Ca/CaM. Our findings provide new insight into how in vitro and in vivo data obtained with KN-93 should be interpreted. They further suggest that other Ca/CaM-dependent, non-CaMKII activities should be considered in KN-93-based mechanism-of-action studies and drug discovery efforts.

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Source
http://dx.doi.org/10.1016/j.jmb.2019.02.001DOI Listing

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