Humanin antagonists: mutants that interfere with dimerization inhibit neuroprotection by Humanin
Humanin antagonists: mutants that interfere with dimerization inhibit neuroprotection by Humanin
复制标题
DOI：
10.1111/j.1460-9568.2004.03298.x
复制
发表时间：
2004-05-01
影响因子：
3.4
通讯作者：
Nishimoto, I
中科院分区：
文献类型：
--
作者：
Hashimoto, Y;Terashita, K;Nishimoto, I
24-残基肽Humanin（HN）通过形成同源二聚体来保护神经元细胞免受各种阿尔茨海默病（AD）基因和Abeta的损伤。我们先前已经表明P3 A、S7 A、C8 A、L9 A、L12 A、T13 A、S14 A和P19 A突变使HN的神经保护功能无效[Yamagishi，Y.，桥本，Y.，Niikura，T. & Nishimoto，I.（2003）Peptides，24，585-595]。在这里，我们研究了这些“无效”突变体是否可以作为显性负突变体发挥作用。同源二聚化缺陷突变体P3 A-、L12 A-、S14 A-和P19 A-HN特异性阻断HN的神经保护作用，但不阻断活性依赖性神经营养因子的神经保护作用。此外，插入S7 A，阻断HN的同源二聚化，而不是插入G5 A的突变取消了L12 A-HN的拮抗作用。虽然L12 A-HN和G5 A/L12 A-HN实际上抑制HN同源二聚化，但S7 A/L12 A-HN没有影响。这些数据表明P3 A-、L12 A-、S14 A-和P19 A-HN通过与HN形成无活性二聚体而作为HN拮抗剂起作用。这项研究提供了一个新的洞察力的了解在体内功能的HN，以及到临床适用的HN中和剂的发展。
The 24-residue peptide Humanin (HN) protects neuronal cells from insults of various Alzheimer's disease (AD) genes and Abeta by forming a homodimer. We have previously shown that P3A, S7A, C8A, L9A, L12A, T13A, S14A and P19A mutations nullify the neuroprotective function of HN [Yamagishi, Y., Hashimoto, Y., Niikura, T. & Nishimoto, I. (2003) Peptides, 24, 585-595]. Here we examined whether any of these 'null' mutants could function as dominant-negative mutants. Homodimerization-defective mutants, P3A-, L12A-, S14A- and P19A-HN, specifically blocked neuroprotection by HN, but not by activity-dependent neurotrophic factor. Furthermore, insertion of S7A, the mutation that blocks the homodimerization of HN, but not insertion of G5A abolished the antagonizing function of L12A-HN. While L12A-HN and G5A/L12A-HN actually inhibited HN homodimerization, S7A/L12A-HN had no effect. These data indicate that P3A-, L12A-, S14A- and P19A-HN function as HN antagonists by forming an inactive dimer with HN. This study provides a novel insight into the understanding of the in vivo function of HN, as well as into the development of clinically applicable HN neutralizers.