AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation.
AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation.
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DOI：
10.1016/j.cmet.2013.08.019
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发表时间：
2013-10-01
期刊：
影响因子：
29
通讯作者：
Hardie DG
中科院分区：
文献类型：
--
作者：
Gowans GJ;Hawley SA;Ross FA;Hardie DG
虽然AMPK的变构激活仅由AMP触发，但已报道ADP和AMP两者的结合促进Thr 172处的磷酸化并抑制去磷酸化。由于ADP和ATP的细胞浓度高于AMP，因此已经提出ADP是促进磷酸化的生理信号，并且变构活化在体内不显著。然而，我们报告说：AMP在抑制Thr 172去磷酸化方面比ADP强10倍;只有AMP增强LKB 1诱导的Thr 172磷酸化;并且AMP甚至在比ATP低1-2个数量级的浓度下也可以引起>10倍的变构激活。我们还提供了证据表明，在Thr 172磷酸化没有变化的条件下，AMP的变构激活可以引起完整细胞中乙酰辅酶A羧化酶磷酸化的增加。因此，AMP是AMPK的真正生理调节剂，变构调节是整个激活机制的重要组成部分。AMP和ADP都能抑制AMPK的去磷酸化和失活，但AMP更有效AMP而不是ADP，促进Thr 172磷酸化和AMPK活化，并且仅通过LKB 1。
While allosteric activation of AMPK is triggered only by AMP, binding of both ADP and AMP has been reported to promote phosphorylation and inhibit dephosphorylation at Thr172. Because cellular concentrations of ADP and ATP are higher than AMP, it has been proposed that ADP is the physiological signal that promotes phosphorylation and that allosteric activation is not significant in vivo. However, we report that: AMP is 10-fold more potent than ADP in inhibiting Thr172 dephosphorylation; only AMP enhances LKB1-induced Thr172 phosphorylation; and AMP can cause >10-fold allosteric activation even at concentrations 1–2 orders of magnitude lower than ATP. We also provide evidence that allosteric activation by AMP can cause increased phosphorylation of acetyl-CoA carboxylase in intact cells under conditions in which there is no change in Thr172 phosphorylation. Thus, AMP is a true physiological regulator of AMPK, and allosteric regulation is an important component of the overall activation mechanism. AMP and ADP both inhibit AMPK dephosphorylation and inactivation, but AMP is more potent AMP, but not ADP, promotes Thr172 phosphorylation and AMPK activation, and only by LKB1 Allosteric activation by AMP is significant even at cellular ATP concentrations Allosteric activation of AMPK by AMP occurs in intact cells
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影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
影响因子：
5.4
作者：
Rolf, Julia;Zarrouk, Marouan;Finlay, David K.;Foretz, Marc;Viollet, Benoit;Cantrell, Doreen A.
通讯作者：
Cantrell, Doreen A.
影响因子：
3.5
作者：
CARLING, D;ZAMMIT, VA;HARDIE, DG
通讯作者：
HARDIE, DG
DOI：
10.1073/pnas.1009705107
发表时间：
2010-11-09
影响因子：
11.1
作者：
Oakhill, Jonathan S.;Chen, Zhi-Ping;Kemp, Bruce E.
通讯作者：
Kemp, Bruce E.
DOI：
10.1126/science.1215327
发表时间：
2012-05-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hawley SA;Fullerton MD;Ross FA;Schertzer JD;Chevtzoff C;Walker KJ;Peggie MW;Zibrova D;Green KA;Mustard KJ;Kemp BE;Sakamoto K;Steinberg GR;Hardie DG
通讯作者：
Hardie DG