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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis
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Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis

机译：阿尔茨海默氏症生存肽Humanin和胰岛素样生长因子结合蛋白3之间的相互作用调节细胞存活和凋亡

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摘要

Insulin-like growth factor-binding protein-3 (IGFBP-3) regulates IGF bioactivity and also independently modulates cell growth and survival. By using a yeast two-hybrid screen to identify IGFBP-3-interacting proteins, we cloned humanin (HN) as an IGFBP-3-binding partner. HN is a 24-aa peptide that has been shown to specifically inhibit neuronal cell death induced by familial Alzheimer's disease mutant genes and amyloid-β (Aβ). The physical interaction of HN with IGFBP-3 was determined to be of high affinity and specificity and was confirmed by yeast mating, dis-placeable pull-down experiments with (His)-6-tagged HN, and ligand blot experiments. Coimmunoprecipitation of IGFBP-3 and HN from mouse testes confirmed the interaction in vivo. In cross-linking experiments, HN bound IGFBP-3 but did not compete with IGF-l-IGFBP-3 binding; competitive ligand dot blot experiments revealed the 18-aa heparin-binding domain of IGFBP-3 as the binding site for HN. Alanine scanning determined that F6A-HN mutant does not bind IGFBP-3. HN but not F6A-HN inhibited IGFBP-3-induced apoptosis in human glioblastoma-A172. In contrast, HN did not suppress IGFBP-3 response in SH-SY5Y neuroblas-toma and mouse cortical primary neurons. In primary neurons, IGFBP-3 markedly potentiated HN rescue ability from Aβ_(1-43) tox-icity. In summary, we have identified an interaction between the survival peptide HN and IGFBP-3 that is pleiotrophic in nature and is capable of both synergistic and antagonistic interaction. This interaction may prove to be important in neurological disease processes and could provide important targets for drug development.
机译：胰岛素样生长因子结合蛋白3（IGFBP-3）调节IGF的生物活性，还独立调节细胞的生长和存活。通过使用酵母双杂交筛选来识别IGFBP-3相互作用蛋白，我们克隆了人胰岛素（HN）作为IGFBP-3结合伴侣。 HN是一种24-aa肽，已被证明可以特异性抑制家族性阿尔茨海默氏病突变基因和淀粉样β（Aβ）诱导的神经元细胞死亡。 HN与IGFBP-3的物理相互作用被确定具有高亲和力和特异性，并通过酵母菌交配，用（His）-6标记的HN进行的可置换下拉实验以及配体印迹实验得到了证实。来自小鼠睾丸的IGFBP-3和HN的共免疫沉淀证实了体内的相互作用。在交联实验中，HN结合了IGFBP-3，但不与IGF-1-IGFBP-3结合竞争。竞争性配体斑点印迹实验表明，IGFBP-3的18-aa肝素结合结构域是HN的结合位点。丙氨酸扫描确定F6A-HN突变体不结合IGFBP-3。 HN而非F6A-HN抑制了人胶质母细胞瘤A172中IGFBP-3诱导的细胞凋亡。相反，HN不能抑制SH-SY5Y神经鞘瘤和小鼠皮质原代神经元的IGFBP-3反应。在原代神经元中，IGFBP-3从Aβ_（1-43）毒性显着增强了HN的拯救能力。总而言之，我们已经确定了存活肽HN和IGFBP-3之间的相互作用，该相互作用本质上是多营养的，并且能够协同和拮抗相互作用。这种相互作用可能在神经系统疾病过程中很重要，并且可以为药物开发提供重要的靶标。

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