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首页> 外文期刊>Journal of Molecular Biology >Long-range effects and functional consequences of stabilizing mutations in the ankyrin repeat domain of I??B??
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Long-range effects and functional consequences of stabilizing mutations in the ankyrin repeat domain of I??B??

机译：I 12 B 14锚蛋白重复结构域中稳定突变的远距离影响和功能后果。

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摘要

Protein domains containing three or more ankyrin repeats (ARs) are ubiquitous in all phyla. Sequence alignments previously identified certain conserved positions, which have been shown to stabilize AR domains and promote their folding. Consensus mutations [Y254L/T257A (YLTA) and C186P/A220P (CPAP)] stabilize the naturally occuring AR domain of human I??B?? to denaturation; however, only the YLTA mutations stabilize the protein to proteasomal degradation. We present results from NMR experiments designed to probe the roles of these consensus mutations in I??B??. According to residual dipolar coupling analysis, the gross structures of the AR domains of both mutants appear to be similar to the wild type (WT). Comparison of chemical shifts of mutant and WT proteins reveals that the YLTA and CPAP consensus mutations cause unexpected long-range effects throughout the AR domains. Backbone dynamics experiments reveal that the YLTA mutations in the sixth AR order the C-terminal PEST sequence on the picosecond-to-nanosecond timescale, compared to either the WT or the CPAP mutant I??B??s. This property is likely the mechanism by which the half-life of YLTA I??B?? is extended in vivo. ?2013 Elsevier Ltd. All rights reserved.
机译：包含三个或多个锚蛋白重复序列​​（ARs）的蛋白质结构域在所有门中普遍存在。序列比对先前鉴定出某些保守位置，已显示其稳定AR结构域并促进其折叠。共有突变[Y254L / T257A（YLTA）和C186P / A220P（CPAP）]稳定了人IβB25的天然存在的AR结构域。变性但是，只有YLTA突变可使蛋白质稳定到蛋白酶体降解。我们提供了NMR实验的结果，该实验被设计用来探测这些共有突变在I 12 B 14中的作用。根据残留偶极耦合分析，两个突变体的AR结构域的总体结构似乎与野生型（WT）相似。比较突变蛋白和野生型蛋白的化学位移，发现YLTA和CPAP共有突变会在整个AR域内引起意想不到的长期影响。骨干动力学实验表明，与WT或CPAP突变体I ?? B ?? s相比，第六个AR中的YLTA突变在皮秒到纳秒的时间尺度上将C端PEST序列排序。该性质可能是YLTA I ?? B ??的半衰期的机理。在体内扩展。 ？2013 Elsevier Ltd.保留所有权利。

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