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Regulation of apoptosis by an intrinsically disordered region of Bcl-xL
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2018-03-05 , DOI: 10.1038/s41589-018-0011-x
Ariele Viacava Follis , Fabien Llambi , Halime Kalkavan , Yong Yao , Aaron H. Phillips , Cheon-Gil Park , Francesca M. Marassi , Douglas R. Green , Richard W. Kriwacki

Intrinsically disordered regions (IDRs) of proteins often regulate function upon post-translational modification (PTM) through interactions with folded domains. An IDR linking two α-helices (α1-α2) of the antiapoptotic protein Bcl-xL experiences several PTMs that reduce antiapoptotic activity. Here, we report that PTMs within the α1-α2 IDR promote its interaction with the folded core of Bcl-xL that inhibits the proapoptotic activity of two types of regulatory targets, BH3-only proteins and p53. This autoregulation utilizes an allosteric pathway whereby, in one direction, the IDR induces a direct displacement of p53 from Bcl-xL coupled to allosteric displacement of simultaneously bound BH3-only partners. This pathway operates in the opposite direction when the BH3-only protein PUMA binds to the BH3 binding groove of Bcl-xL, directly displacing other bound BH3-only proteins, and allosterically remodels the distal site, displacing p53. Our findings show how an IDR enhances functional versatility through PTM-dependent allosteric regulation of a folded protein domain.



中文翻译:

Bcl-xL内在无序区对细胞凋亡的调节

蛋白质的内在无序区域(IDR)通常通过与折叠域的相互作用来调节翻译后修饰(PTM)时的功能。连接抗凋亡蛋白Bcl-xL的两个α螺旋(α1-α2)的IDR经历了几种降低抗凋亡活性的PTM。在这里,我们报告说,α1-α2IDR中的PTM促进其与Bcl-xL折叠核心的相互作用,从而抑制两种类型的调控靶标(仅BH3的蛋白质)和p53的促凋亡活性。这种自动调节利用一种变构途径,从而在一个方向上,IDR诱导p53从Bcl-xL发生直接置换,与同时结合的仅BH3伴侣的变构置换相结合。当仅BH3的蛋白质PUMA与Bcl-xL的BH3结合槽结合时,该途径沿相反的方向起作用,直接置换其他结合的仅BH3的蛋白质,并变构地重塑远端位点,置换p53。我们的发现表明,IDR如何通过依赖PTM的折叠蛋白结构域的变构调节来增强功能的多功能性。

更新日期:2018-03-06
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