A tripartite motif protein TRIM11 binds and destabilizes Humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults
A tripartite motif protein TRIM11 binds and destabilizes Humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults
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DOI：
10.1046/j.1460-9568.2003.02553.x
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发表时间：
2003-03-01
影响因子：
3.4
通讯作者：
Nishimoto, I
中科院分区：
文献类型：
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作者：
Niikura, T;Hashimoto, Y;Nishimoto, I
Humanin（HN）是一种新发现的神经保护肽，可特异性抑制阿尔茨海默病（AD）相关的神经毒性。通过免疫印迹和免疫组织化学分析，在人类AD大脑以及小鼠睾丸和结肠中检测到HN肽。通过酵母双杂交筛选，我们鉴定出TRIM 11是一个新的HN相互作用蛋白。TRIM 11是包含三重基序的蛋白质家族（TRIM）的成员，其由一个RING指结构域（其是一种推定的E3泛素连接酶）、一个B-box结构域、一个卷曲螺旋结构域和一个B30.2结构域组成。TRIM 11中B30.2结构域的缺失消除了与HN的相互作用，而单独的B30.2结构域不与HN相互作用。对于它们的相互作用，至少卷曲螺旋结构域与B30.2结构域一起是必不可少的。通过TRIM 11的共表达，谷胱甘肽S -转移酶融合的或EGFP融合的HN肽或普通HN的细胞内水平急剧降低。通过删除第一共有半胱氨酸或蛋白酶体抑制剂处理来破坏RING指结构域显著降低了TRIM 11对HN细胞内水平的影响。这些结果表明TRIM 11通过泛素介导的蛋白降解途径在细胞内HN水平的调节中起作用。
Humanin (HN) is a newly identified neuroprotective peptide that specifically suppresses Alzheimer's disease (AD)-related neurotoxicity. HN peptide has been detected in the human AD brain as well as in mouse testis and colon by immunoblot and immunohistochemical analyses. By means of yeast two-hybrid screening, we identified TRIM11 as a novel HN-interacting protein. TRIM11, which is a member of protein family containing a tripartite motif (TRIM), is composed of a RING finger domain, which is a putative E3 ubiquitin ligase, a B-box domain, a coiled-coil domain and a B30.2 domain. Deletion of the B30.2 domain in TRIM11 abolished the interaction with HN, whereas the B30.2 domain alone did not interact with HN. For their interaction, at least the coiled-coil domain was indispensable together with the B30.2 domain. The intracellular level of glutathione S -transferase-fused or EGFP-fused HN peptides or plain HN was drastically reduced by the coexpression of TRIM11. Disruption of the RING finger domain by deleting the first consensus cysteine or proteasome inhibitor treatment significantly diminished the effect of TRIM11 on the intracellular level of HN. These results suggest that TRIM11 plays a role in the regulation of intracellular HN level through ubiquitin-mediated protein degradation pathways.