Liberated PKA Catalytic Subunits Associate with the Membrane via Myristoylation to Preferentially Phosphorylate Membrane Substrates.
Liberated PKA Catalytic Subunits Associate with the Membrane via Myristoylation to Preferentially Phosphorylate Membrane Substrates.
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DOI：
10.1016/j.celrep.2017.03.070
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发表时间：
2017-04-18
期刊：
影响因子：
8.8
通讯作者：
Zhong H
中科院分区：
文献类型：
--
作者：
Tillo SE;Xiong WH;Takahashi M;Miao S;Andrade AL;Fortin DA;Yang G;Qin M;Smoody BF;Stork PJS;Zhong H
蛋白激酶A（PKA）在神经元中具有多种功能。在静息状态下，PKA的亚细胞定位由A-激酶锚定蛋白（AKAP）控制。然而，PKA激活后的动力学仍然知之甚少。在这里，我们报告说，在神经元树突的cAMP的升高导致了显着比例的PKA催化亚基（PKA-C）分子被释放的调节亚基（PKA-R）。释放的PKA-C通过N-末端豆蔻酰化与膜结合。这种膜结合不需要PKA-R和AKAP之间的相互作用。它减缓PKA-C的流动性并富集膜上的激酶活性。与胞质底物相比，膜驻留PKA底物优先磷酸化。最后，PKA-C的豆蔻酰化对于正常的突触功能和可塑性至关重要。我们认为PKA-C的激活依赖性结合使膜成为一个独特的PKA信号区室。PKA-C的受限移动性可能与AKAP锚定协同作用，以确定神经元中的特定PKA功能。
Protein kinase A (PKA) has diverse functions in neurons. At rest, the subcellular localization of PKA is controlled by A-kinase anchoring proteins (AKAPs). However, the dynamics of PKA upon activation remain poorly understood. Here we report that elevation of cAMP in neuronal dendrites causes a significant percentage of the PKA catalytic subunit (PKA-C) molecules to be released from the regulatory subunit (PKA-R). Liberated PKA-C becomes associated with the membrane via N-terminal myristoylation. This membrane association does not require the interaction between PKA-R and AKAPs. It slows the mobility of PKA-C and enriches kinase activity on the membrane. Membrane-residing PKA substrates are preferentially phosphorylated compared to cytosolic substrates. Finally, the myristoylation of PKA-C is critical for normal synaptic function and plasticity. We propose that activation-dependent association of PKA-C renders the membrane a unique PKA-signaling compartment. Constrained mobility of PKA-C may synergize with AKAP anchoring to determine specific PKA function in neurons.