An Isoform-Specific Myristylation Switch Targets Type II PKA Holoenzymes to Membranes.
An Isoform-Specific Myristylation Switch Targets Type II PKA Holoenzymes to Membranes.
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异构体特异性十四烷基化开关将 II 型 PKA 全酶靶向膜。
DOI：
10.1016/j.str.2015.07.007
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Taylor,SusanS
中科院分区：
文献类型：
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作者：
Zhang,Ping;Ye,Feng;Bastidas,AdamC;Kornev,AlexandrP;Wu,Jian;Ginsberg,MarkH;Taylor,SusanS
环腺苷酸依赖性蛋白激酶（PKA）部分受其催化（C）亚基N-末端肉豆蔻酰化的调节。关于豆蔻酰化在PKA膜靶向中的作用的结构信息有限。在哺乳动物细胞中，存在四种功能上非冗余的PKA调节亚基（RIα、RIβ、RIIα和RIIβ）。PKA在细胞中组装成无活性的R2 C2全酶。为了探索N-肉豆蔻基化在PKA全酶膜靶向中的作用，我们解析了RIα：myrC和RIIβ2：myrC 2的晶体结构，并表明myrC中的N-末端肉豆蔻基化位点作为一个灵活的“开关”，可以潜在地被动员用于RII而不是RI全酶的膜锚定。此外，我们合成了纳米盘，并通过电子显微镜显示，膜靶向通过肉豆蔻酸是特定的RII全酶。这种膜锚定肉豆蔻基化开关不依赖于通过其他机制将PKA靶向至膜的A激酶锚定蛋白（AKAP）。
Cyclic AMP-dependent protein kinase (PKA) is regulated in part by N-terminal myristylation of its catalytic (C) subunit. Structural information about the role of myristylation in membrane targeting of PKA has been limited. In mammalian cells there are four functionally non-redundant PKA regulatory subunits (RIα, RIβ, RIIα, and RIIβ). PKA is assembled as an inactive R2C2holoenzyme in cells. To explore the role of N-myristylation in membrane targeting of PKA holoenzymes, we solved crystal structures of RIα:myrC and RIIβ2:myrC2, and showed that the N-terminal myristylation site in the myrC serves as a flexible "switch" that can potentially be mobilized for membrane anchoring of RII, but not RI, holoenzymes. Furthermore, we synthesized nanodiscs and showed by electron microscopy that membrane targeting through the myristic acid is specific for the RII holoenzyme. This membrane-anchoring myristylation switch is independent of A Kinase Anchoring Proteins (AKAPs) that target PKA to membranes by other mechanisms.