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【答案】应助回帖
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ygy19901025: 金币+100, 翻译EPI+1, ★★★★★最佳答案 2014-03-13 22:11:24
Abstract
摘要
Glycogen synthase kinase-3β (GSK-3β), a key regulator of neuronal apoptosis, is inhibited by the phosphorylation of Ser-9/Ser-389 and was recently shown to be cleaved by calpain at the N terminus, leading to its subsequent activation.
糖原合成酶激酶-3β（GSK-3β），是神经元凋亡的关键调控物质，会受到Ser-9/Ser-389位点磷酸化的抑制，最近发现它可以被钙蛋白酶在N端切断，这一反应随后将其活化。
In this study calpain was found to cleave GSK-3β not only at the N terminus but also at the C terminus, and cleavage sites were identified at residues Thr-38–Thr-39 and Ile-384–Gln-385.
本研究中发现钙蛋白酶不仅能切断GSK-3β的N端，还可以切开其C末端，并确定了其酶切位点为Thr-38/Thr-39和Ile-384/Gln-385这两对氨基酸残基之间。
Furthermore, the cleavage of GSK-3β occurred in tandem with Ser-9 dephosphorylation during cerebellar granule neuron apoptosis.
另外，GSK-3β的切断是与Ser-9的去磷酸化过程一起，在小脑颗粒神经元凋亡过程中发生的。
Increasing Ser-9 phosphorylation of GSK-3β by inhibiting phosphatase 1/2A or pretreating with purified active Akt inhibited calpain-mediated cleavage of GSK-3β at both N and C termini, whereas non-phosphorylatable mutant GSK-3β S9A facilitated its cleavage.
通过抑制磷酸酶1/2A或用纯化过的活化态的Akt进行预处理，来提高Ser-9的磷酸化程度，可以抑制钙蛋白酶介导的GSK-3β在N末端和C末端发生的断裂，然而不可磷酸化的GSK-3β突变体S9A则能够促进其断裂。
In contrast, Ser-389 phosphorylation selectively inhibited the cleavage of GSK-3β at the C terminus but not the N terminus.
相比之下，Ser-389的磷酸化选择性的抑制了GSK-3β在C末端的断裂，而对N末端没有影响。
Calpain-mediated cleavage resulted in three truncated products, all of which contained an intact kinase domain: ΔN-GSK-3β (amino acids 39–420), ΔC-GSK-3β (amino acids 1–384), and ΔN/ΔC-GSK-3β (amino acids 39–384).
钙蛋白酶介导的断裂产生了三种酶切产物，它们都包含了完整的激酶结构域：ΔN-GSK-3β (氨基酸残基39–420), ΔC-GSK-3β (氨基酸残基1–384), 以及ΔN/ΔC-GSK-3β (氨基酸残基39–384).
All three truncated products showed increased kinase and pro-apoptotic activity, with ΔN/ΔC-GSK-3β being the most active form.
所有这三种酶切产物显示出了更高的激酶活性以及促凋亡活性，其中 ΔN/ΔC-GSK-3β 活性最高。
This observation suggests that the GSK-3β C terminus acts as an autoinhibitory domain similar to the N terminus.
这一现象显示出GSK-3β的C末端与N末端类似，都是一种起自我抑制作用的结构域。
Taken together, these findings demonstrate that calpain-mediated cleavage activates GSK-3β by removing its N- and C-terminal autoinhibitory domains and that Ser-9 phosphorylation inhibits the cleavage of GSK-3β at both termini.
综上所述，这些发现显示出：钙蛋白酶介导的断裂移除了N末端和C末端的自我抑制结构域，从而活化了GSK-3β，Ser-9的磷酸化作用抑制了GSK-3β的两个末端发生的断裂反应。
In contrast, Ser-389 phosphorylation inhibits only C-terminal cleavage but not N-terminal cleavage.
相比之下，Ser-389的磷酸化只能一直C末端的断裂，而不抑制N末端断裂。
These findings also identify a mechanism by which site-specific phosphorylation and calpain-mediated cleavage operate in concert to regulate GSK-3β activity.
这些发现还确定了一个位点特异性磷酸化作用和钙蛋白酶介导的断裂作用一齐调节GSK-3β的活性的作用机制。 |
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