Deconvoluting AMP-activated protein kinase (AMPK) adenine nucleotide binding and sensing
文献类型：期刊论文
| 作者 | Gu, Xin2; Yan, Yan2,3; Novick, Scott J.1; Kovach, Amanda2; Goswami, Devrishi1; Ke, Jiyuan2; Tan, M. H. Eileen2,4; Wang, Lili2; Li, Xiaodan2; de Waal, Parker W.2 |
| 刊名 | JOURNAL OF BIOLOGICAL CHEMISTRY
 |
| 出版日期 | 2017-07-28 |
| 卷号 | 292期号:30页码:12653-12666 |
| ISSN号 | 0021-9258 |
| 关键词 | AMP AMP-activated kinase (AMPK) ATP energy metabolism protein kinase CBS HDX-MS NADPH |
| DOI | 10.1074/jbc.M117.793018 |
| 文献子类 | Article |
| 英文摘要 | AMP-activated protein kinase (AMPK) is a central cellular energy sensor that adapts metabolism and growth to the energy state of the cell. AMPK senses the ratio of adenine nucleotides (adenylate energy charge) by competitive binding of AMP, ADP, and ATP to three sites (CBS1, CBS3, and CBS4) in its -subunit. Because these three binding sites are functionally interconnected, it remains unclear how nucleotides bind to individual sites, which nucleotides occupy each site under physiological conditions, and how binding to one site affects binding to the other sites. Here, we comprehensively analyze nucleotide binding to wild-type and mutant AMPK protein complexes by quantitative competition assays and by hydrogen-deuterium exchange MS. We also demonstrate that NADPH, in addition to the known AMPK ligand NADH, directly and competitively binds AMPK at the AMP-sensing CBS3 site. Our findings reveal how AMP binding to one site affects the conformation and adenine nucleotide binding at the other two sites and establish CBS3, and not CBS1, as the high affinity exchangeable AMP/ADP/ATP-binding site. We further show that AMP binding at CBS4 increases AMP binding at CBS3 by 2 orders of magnitude and reverses the AMP/ATP preference of CBS3. Together, these results illustrate how the three CBS sites collaborate to enable highly sensitive detection of cellular energy states to maintain the tight ATP homeostastis required for cellular metabolism. |
| WOS关键词 | PARKINSON-WHITE-SYNDROME ; GAMMA-SUBUNIT ISOFORMS ; ACETYL-COA CARBOXYLASE ; STRUCTURAL BASIS ; METABOLIC DISEASES ; EXERCISE MIMETICS ; GLYCOGEN-STORAGE ; R225W MUTATION ; ENERGY-CHARGE ; LIFE-SPAN |
| 资助项目 | Francis Crick Institute[00000000] ; Cancer Research UK[FC001211] ; United Kingdom Medical Research Council[FC001211] ; Wellcome Trust[FC001211] ; Van Andel Research Institute[00000000] ; Ministry of Science and Technology (China)[2012ZX09301001] ; Ministry of Science and Technology (China)[2012CB910403] ; Ministry of Science and Technology (China)[2013CB910600] ; Ministry of Science and Technology (China)[XDB08020303] ; Ministry of Science and Technology (China)[2013ZX09507001] ; National Science Foundation[91217311] ; National Institute of Health[DK071662] ; National Institute of Health[GM102545] ; National Institute of Health[GM104212] |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| 出版者 | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC |
| WOS记录号 | WOS:000406636900029 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272553]  |
| 专题 | 药物靶标结构与功能中心 |
| 通讯作者 | Melcher, Karsten |
| 作者单位 | 1.Scripps Res Inst, Translat Res Inst, Dept Mol Med, Jupiter, FL 33458 USA; 2.Van Andel Res Inst, Ctr Canc & Cell Biol, Labs Struct Sci & Struct Biol & Biochem, 333 Bostwick Ave Northeast, Grand Rapids, MI 49503 USA; 3.Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, VARI SIMM Ctr,Ctr Struct & Funct Drug Targets, Shanghai 201203, Peoples R China; 4.Francis Crick Inst, 1 Midland Rd, London NW1 1AT, England |
| 推荐引用方式 GB/T 7714 | Gu, Xin,Yan, Yan,Novick, Scott J.,et al. Deconvoluting AMP-activated protein kinase (AMPK) adenine nucleotide binding and sensing[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2017,292(30):12653-12666. |
| APA | Gu, Xin.,Yan, Yan.,Novick, Scott J..,Kovach, Amanda.,Goswami, Devrishi.,...&Melcher, Karsten.(2017).Deconvoluting AMP-activated protein kinase (AMPK) adenine nucleotide binding and sensing.JOURNAL OF BIOLOGICAL CHEMISTRY,292(30),12653-12666. |
| MLA | Gu, Xin,et al."Deconvoluting AMP-activated protein kinase (AMPK) adenine nucleotide binding and sensing".JOURNAL OF BIOLOGICAL CHEMISTRY 292.30(2017):12653-12666. |
入库方式： OAI收割
来源：上海药物研究所
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