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DAXX是一种新型的蛋白质折叠促进因子
2021-08-22 13:14

美国宾夕法尼亚大学Xiaolu Yang课题组发现,DAXX是一种新型的蛋白质折叠促进因子。相关论文于2021年8月18日在线发表在《自然》杂志上。

研究人员发现DAXX,一种多聚天冬氨酸/谷氨酸(polyD/E)蛋白,涉及不同的细胞过程,并拥有几种蛋白质折叠的活性。DAXX防止聚集,溶解预先存在的聚集物,并解开模型底物和神经变性相关蛋白的错误折叠蛋白。值得注意的是,DAXX能有效地防止和逆转其体内验证的客户蛋白、肿瘤抑制因子p53及其主要拮抗剂MDM2的聚集。DAXX还能恢复肿瘤相关的、易聚集的p53突变体的原始构象和功能,减少其致癌性。这些DAXX的活动是不依赖ATP的,而是依赖于polyD/E区域。

其他polyD/E蛋白,包括ANP32A和SET,也可以作为独立的、不依赖ATP的分子伴侣、分解酶和解折叠酶发挥作用。因此,polyD/E蛋白可能构成一个多功能的蛋白质质量控制系统,通过独特的机制运作。

据介绍,蛋白质质控系统对细胞功能和机体健康至关重要。目前,大多数已知的蛋白质质量控制系统是多组分的机器,通过ATP调节的局部蛋白质相互作用来防止聚集和促进折叠,很少有系统能通过不同的机制广泛地使蛋白质折叠。此外,含有带电polyD/E区域的蛋白质在真核生物蛋白质组中很常见,但其生化活性仍未确定。

附:英文原文

Title: DAXX represents a new type of protein-folding enabler

Author: Huang, Liangqian, Agrawal, Trisha, Zhu, Guixin, Yu, Sixiang, Tao, Liming, Lin, JiaBei, Marmorstein, Ronen, Shorter, James, Yang, Xiaolu

Issue&Volume: 2021-08-18

Abstract: Protein quality control systems are crucial for cellular function and organismal health. At present, most known protein quality control systems are multicomponent machineries that operate via ATP-regulated interactions with non-native proteins to prevent aggregation and promote folding1, and few systems that can broadly enable protein folding by a different mechanism have been identified. Moreover, proteins that contain the extensively charged poly-Asp/Glu (polyD/E) region are common in eukaryotic proteomes2, but their biochemical activities remain undefined. Here we show that DAXX, a polyD/E protein that has been implicated in diverse cellular processes3,4,5,6,7,8,9,10, possesses several protein-folding activities. DAXX prevents aggregation, solubilizes pre-existing aggregates and unfolds misfolded species of model substrates and neurodegeneration-associated proteins. Notably, DAXX effectively prevents and reverses aggregation of its in vivo-validated client proteins, the tumour suppressor p53 and its principal antagonist MDM2. DAXX can also restore native conformation and function to tumour-associated, aggregation-prone p53 mutants, reducing their oncogenic properties. These DAXX activities are ATP-independent and instead rely on the polyD/E region. Other polyD/E proteins, including ANP32A and SET, can also function as stand-alone, ATP-independent molecular chaperones, disaggregases and unfoldases. Thus, polyD/E proteins probably constitute a multifunctional protein quality control system that operates via a distinctive mechanism.

DOI: 10.1038/s41586-021-03824-5

Source: https://www.nature.com/articles/s41586-021-03824-5

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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