Inhibition of APP intracellular domain (AICD) transcriptional activity via covalent conjugation with Nedd8
Inhibition of APP intracellular domain (AICD) transcriptional activity via covalent conjugation with Nedd8
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DOI：
10.1016/j.bbrc.2007.12.066
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发表时间：
2008-02-22
影响因子：
3.1
通讯作者：
Choi, Cheol Yong
中科院分区：
文献类型：
--
作者：
Lee, Mi-Ra;Lee, Deresa;Choi, Cheol Yong
淀粉样前体蛋白(APP)被γ-分泌酶处理后产生APP胞内域(AICD)，它作为转录因子在定位到细胞核后激活靶基因。在这项研究中，我们证明了AICD可以通过与泛素样蛋白Nedd8的共价连接来修饰。结构域分析和碱基定点替换表明，APP C端C99片段的多个赖氨酸残基包括AICD是Nedd8接合的受体序列。Nedd8结合抑制了AICD介导的转录激活。此外，Nedd8的表达不改变缺失AICD突变体的转录活性。AICD的NEDD8结合抑制了其与Fe65的相互作用，从而导致AICD-Fe65-Tip60复合体的形成障碍，从而抑制了靶基因的转录激活。这些结果说明了AICD转录活性可能通过与Nedd8的共价结合来调节的调控机制。(C)2007 Elsevier Inc.保留所有权利。
The processing of amyloid precursor protein (APP) by gamma-secretase generates the APP intracellular domain (AICD), which functions as a transcriptional factor for target gene activation following localization into the nucleus. In this study, we demonstrate that AICD could be modified via covalent conjugation with Nedd8, a ubiquitin-like protein. Domain analysis and site-directed substitution of neddylation sites showed that multiple lysine residues of the APP C-terminal C99 fragment including AICD were acceptor sequences for Nedd8 conjugation. AICD-mediated transcriptional activation was inhibited by Nedd8 conjugation. Furthermore, the transcriptional activity of the neddylation-defective AICD mutant was not altered by Nedd8 expression. Nedd8 conjugation of AICD inhibited its interaction with Fe65, and consequently resulted in the impairment of AICD-Fe65-Tip60 complex formation for the transcriptional activation of the target gene. These results illustrate the regulatory mechanisms by which AICD transcriptional activity might be regulated via covalent conjugation with Nedd8. (c) 2007 Elsevier Inc. All rights reserved.