A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias
A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias
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DOI：
10.1016/s0960-9822(03)00249-5
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发表时间：
2003-05-13
期刊：
影响因子：
9.2
通讯作者：
Hardie, DG
中科院分区：
文献类型：
--
作者：
Hudson, ER;Pan, DA;Hardie, DG
AMP 激活蛋白激酶 (AMPK) 是一种 Alphagamma 异三聚体，可在低细胞能量状态下激活，并影响从能量需求过程向分解代谢的转变 [1]。虽然它主要受 AMP 和 ATP 调节，但高肌糖原也被证明可以抑制其激活 [2, 3]。 gamma2 和 gamma3 亚基异构体的突变分别导致与人类心脏糖原储存异常相关的心律失常 [4-7] 和猪肌肉糖原升高 [8]。现已在 β 亚基中鉴定出推定的糖原结合结构域 (GBD)。缺乏 GBD 的截短 β 亚基与 α 和 γ 亚基的共表达产生了活性且正常调节的复合物。然而，α和γ与全长β的共表达导致AMPK在大细胞质内含物中积累，可以用抗糖原或抗糖原合酶抗体进行复染。这些内含物不受增加或消除激酶活性的突变的影响，并且使用缺乏 GBD 的截短 β 亚基也未观察到这些内含物。我们的结果表明，GBD 结合糖原，当激酶过度表达时，会导致异常的含糖原包涵体。这些可能与伽马2突变的心脏病患者体内糖原储存体异常有关。
The AMP-activated protein kinase (AMPK) is an alphabetagamma heterotrimer that is activated by low cellular energy status and affects a switch away from energy-requiring processes and toward catabolism [1]. While it is primarily regulated by AMP and ATP, high muscle glycogen has also been shown to repress its activation [2, 3]. Mutations in the gamma2 and gamma3 subunit isoforms lead to arrhythmias associated with abnormal glycogen storage in human heart [4-7] and elevated glycogen in pig muscle [8], respectively. A putative glycogen binding domain (GBD) has now been identified in the beta subunits. Coexpression of truncated beta subunits lacking the GBD with alpha and gamma subunits yielded complexes that were active and normally regulated. However, coexpression of alpha and gamma with full-length beta caused accumulation of AMPK in large cytoplasmic inclusions that could be counterstained with anti-glycogen or anti-glycogen synthase antibodies. These inclusions were not affected by mutations that increased or abolished the kinase activity and were not observed by using truncated beta subunits lacking the GBD. Our results suggest that the GBD binds glycogen and can lead to abnormal glycogen-containing inclusions when the kinase is overexpressed. These may be related to the abnormal glycogen storage bodies seen in heart disease patients with gamma2 mutations.