Structure of mammalian AMPK and its regulation by ADP.
Structure of mammalian AMPK and its regulation by ADP.
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DOI：
10.1038/nature09932
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发表时间：
2011-04-14
期刊：
影响因子：
64.8
通讯作者：
Gamblin, Steven J.
中科院分区：
文献类型：
--
作者：
Xiao, Bing;Sanders, Matthew J.;Underwood, Elizabeth;Heath, Richard;Mayer, Faith V.;Carmena, David;Jing, Chun;Walker, Philip A.;Eccleston, John F.;Haire, Lesley F.;Saiu, Peter;Howell, Steven A.;Aasland, Rein;Martin, Stephen R.;Carling, David;Gamblin, Steven J.
异源三聚体AMP激活蛋白激酶（AMPK）在调节细胞能量代谢中起关键作用;响应于细胞内ATP水平的下降，其激活能量产生途径并抑制能量消耗过程。AMPK与许多与能量代谢相关的疾病有关，包括2型糖尿病、肥胖症和最近的癌症。AMPK通过激酶结构域内活化环的磷酸化从无活性形式转化为催化活性形式; AMP与γ调节结构域结合促进上游激酶的磷酸化，保护酶免于去磷酸化以及引起变构活化。在这里，我们表明，ADP结合到调节结构域上的两个可交换的AXP结合位点之一，保护酶的去磷酸化，虽然它不会导致变构激活。我们的研究表明，活性AMPK与ADP的结合比与Mg·ATP的结合更紧密，这解释了在Mg·ATP浓度高于ADP浓度且远高于AMP浓度的生理条件下，该酶是如何被调节的。我们已经确定了活性AMPK复合物的晶体结构。它显示了激酶结构域的激活环如何通过调节结构域稳定，以及激酶接头区如何与调节核苷酸结合位点相互作用，调节核苷酸结合位点介导对去磷酸化的保护。从我们的生物化学和结构数据，我们开发了一个模型，用于细胞的能量状态如何调节AMPK活性（补充图1）。
The heterotrimeric AMP-activated protein kinase (AMPK) plays a key role in regulating cellular energy metabolism; in response to a fall in intracellular ATP levels it activates energy producing pathways and inhibits energy consuming processes. AMPK has been implicated in a number of diseases related to energy metabolism including type 2 diabetes, obesity and, most recently, cancer. AMPK is converted from an inactive to catalytically competent form by phosphorylation of the activation loop within the kinase domain; AMP binding to the γ regulatory domain promotes phosphorylation by the upstream kinase, protects the enzyme against dephosphorylation as well as causing allosteric activation. We show here that ADP binding to just one of the two exchangeable AXP binding sites on the regulatory domain protects the enzyme from dephosphorylation, although it does not lead to allosteric activation. Our studies show that active AMPK displays significantly tighter binding to ADP than to Mg.ATP, explaining how the enzyme is regulated under physiological conditions where the concentration of Mg.ATP is higher than that of ADP and much higher than that of AMP. We have determined the crystal structure of an active AMPK complex. It shows how the activation loop of the kinase domain is stabilized by the regulatory domain and how the kinase linker region interacts with the regulatory nucleotide binding site that mediates protection against dephosphorylation. From our biochemical and structural data we develop a model for how the energy status of a cell regulates AMPK activity (Supplementary Fig. 1).
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影响因子：
4.1
作者：
Sanders, Matthew J.;Grondin, Pascal O.;Carling, David
通讯作者：
Carling, David
DOI：
10.1073/pnas.1009705107
发表时间：
2010-11-09
影响因子：
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