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首页> 外文期刊>Journal of Molecular Biology >The KN-93 Molecule Inhibits Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity by Binding to Ca2+/CaM
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The KN-93 Molecule Inhibits Calcium/Calmodulin-Dependent Protein Kinase II (CaMKII) Activity by Binding to Ca2+/CaM

机译：KN-93分子通过与CA2 + /凸轮结合抑制钙/钙调蛋白依赖性蛋白激酶II（CAMKII）活性

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摘要

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 (Ca2+/CaM) through a direct binding mechanism involving a regulatory C-terminal alpha-helix in CaMKII. The Ca2+/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 Ca2+/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 Ca2+/CaM and not to CaMKII. This binding would disrupt the ability of Ca2+/CaM to interact with CaMKII, effectively inhibiting CaMKII activation. Our findings also indicated that KN-93 can specifically compete with a CaMKII delta-derived peptide for binding to Ca2+/CaM. As indicated by the surface plasmon resonance and isothermal titration calorimetry data, apparently at least two KN-93 molecules can bind to Ca2+/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 Ca2+/CaM-dependent, non-CaMKII activities should be considered in KN-93 based mechanism-of-action studies and drug discovery efforts. (C) 2019 Elsevier Ltd. All rights reserved.
机译：钙/钙调蛋白依赖性蛋白激酶II（CAMKII）是一种多功能丝氨酸/苏氨酸蛋白激酶，其在各种细胞过程中透射钙信号。 Camkii通过钙 - 结合的钙调蛋白（CA2 + / Cam）激活，通过涉及Camkii的调节C末端α-螺旋的直接结合机制。 Ca2 + / Cam结合触发临时苏氨酸残基的转磷酸化，临时凸轮结合位点，导致Camkii的自动激活状态。其在病理生理过程中的关键作用的证明已经提升了CAMKII，以众多疾病管理的关键目标。分子KN-93是用于研究CAMKII的细胞和体内功能的最广泛使用的抑制剂。众所周知，KN-93直接与CaMKII结合，从而通过与CA2 + /凸轮竞争来防止激酶活化。在此，我们使用表面等离子体共振，NMR和等温滴定热量来表征该假发的相互作用。我们的结果表明，KN-93直接与CA2 + /凸轮粘合，而不是Camkii。这种绑定会破坏CA2 + / CAM与CAMKII相互作用的能力，有效地抑制CAMKII激活。我们的研究结果表明，KN-93可以与CAMKIIδ衍生的肽特异性竞争，用于与CA2 + /凸轮结合。如表面等离子体谐振和等温滴定热量数据所示，显然至少两个KN-93分子可以与CA2 + /凸轮结合。我们的调查结果提供了新的洞察，以如何解释KN-93获得的体外和体内数据。他们进一步建议，基于KN-93的行动机制和药物发现努力，应考虑其他CA2 + / CAM依赖的非CAMKII活动。 （c）2019 Elsevier Ltd.保留所有权利。

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