The Mitochondrial-Derived Peptides, HumaninS14G and Small Humanin-like Peptide 2, Exhibit Chaperone-like Activity.
The Mitochondrial-Derived Peptides, HumaninS14G and Small Humanin-like Peptide 2, Exhibit Chaperone-like Activity.
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DOI：
10.1038/s41598-017-08372-5
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发表时间：
2017-08-10
影响因子：
4.6
通讯作者：
Langen R
中科院分区：
文献类型：
--
作者：
Okada AK;Teranishi K;Lobo F;Isas JM;Xiao J;Yen K;Cohen P;Langen R
线粒体衍生肽（MDPs）及其类似物已成为淀粉样蛋白疾病模型中具有保护作用的广谱应激反应因子。MDP的细胞保护功能通常归因于抗凋亡活性，然而，人们对其通过与淀粉样蛋白直接相互作用促进细胞未折叠蛋白反应的能力知之甚少。在这里，我们探讨了MDP类似物humaninS14G （HNG）和MDP小人源样肽2 （SHLP2）对胰岛淀粉样多肽（IAPP）错误折叠的影响，IAPP是2型糖尿病（T2DM）的一个关键致病步骤。我们的硫黄素T荧光研究表明，HNG在高亚化学计量浓度下抑制IAPP错误折叠。种子荧光和共沉淀研究表明，MDPs阻断淀粉样蛋白的播种，并直接结合错误折叠的具有播种能力的IAPP物种。此外，我们的电子顺磁共振光谱和圆二色性数据表明，MDPs不通过结合IAPP单体起作用。综上所述，我们的研究结果揭示了一种新的伴侣样活性，其中这些MDPs特异性地靶向错误折叠的淀粉样蛋白种子来抑制IAPP错误折叠，这与直接的抗凋亡活性和有益的代谢作用一起，使HNG和SHLP2成为T2DM治疗的令人兴奋的前景。这些数据还表明，MDP家族中的其他线粒体应激反应因子可能适合开发成蛋白质错误折叠疾病的治疗方法。
Mitochondrial-derived peptides (MDPs) and their analogs have emerged as wide-spectrum, stress response factors protective in amyloid disease models. MDP cytoprotective functions are generally attributed to anti-apoptotic activity, however, little is known about their capacity to facilitate the cell’s unfolded protein response via direct interactions with amyloidogenic proteins. Here, we explored the effects of the MDP-analog, humaninS14G (HNG), and the MDP, small humanin-like peptide 2 (SHLP2), on the misfolding of islet amyloid polypeptide (IAPP), a critical pathogenic step in type 2 diabetes mellitus (T2DM). Our thioflavin T fluorescence studies show that HNG inhibits IAPP misfolding at highly substoichiometric concentrations. Seeded fluorescence and co-sedimentation studies demonstrate MDPs block amyloid seeding and directly bind misfolded, seeding-capable IAPP species. Furthermore, our electron paramagnetic resonance spectroscopy and circular dichroism data indicate MDPs do not act by binding IAPP monomers. Taken together our results reveal a novel chaperone-like activity wherein these MDPs specifically target misfolded amyloid seeds to inhibit IAPP misfolding which, along with direct anti-apoptotic activity and beneficial metabolic effects, make HNG and SHLP2 exciting prospects as T2DM therapeutics. These data also suggest that other mitochondrial stress response factors within the MDP family may be amenable to development into therapeutics for protein-misfolding diseases.