Many chaperones favour binding to hydrophobic sequences that are flanked by basic residues while disfavouring acidic residues. However, the origin of this bias in protein quality control remains poorly understood. Here, we show that while acidic residues are the most efficient aggregation inhibitors, they are also less compatible with globular protein structure than basic amino acids. As a result, while acidic residues allow for chaperone‐independent control of aggregation, their use is structurally limited. Conversely, we find that, while being more compatible with globular structure, basic residues are not sufficient to autonomously suppress protein aggregation. Using Hsp70, we show that chaperones with a bias towards basic residues are structurally adapted to prioritize aggregating sequences whose structural context forced the use of the less effective basic residues. The hypothesis that emerges from our analysis is that the bias of many chaperones for basic residues results from fundamental thermodynamic and kinetic constraints of globular structure. This also suggests the co‐evolution of basic residues and chaperones allowed for an expansion of structural variety in the protein universe.

中文翻译：

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酸性残基的自主聚集抑制解释了伴侣分子偏爱碱性残基的原因。

许多伴侣分子倾向于与侧翼碱性残基的疏水序列结合，而不利于酸性残基。但是，这种对蛋白质质量控​​制偏见的根源仍然知之甚少。在这里，我们表明，尽管酸性残基是最有效的聚集抑制剂，但与碱性氨基酸相比，它们与球状蛋白质结构的相容性也较低。结果，尽管酸性残基允许分子伴侣独立控制聚集，但其使用在结构上受到限制。相反，我们发现，虽然与球状结构更相容，但基本残基不足以自主抑制蛋白质聚集。使用Hsp70，我们表明，对基本残基有偏见的分子伴侣在结构上适合于优先排序聚集序列，其结构背景迫使使用效果较差的基本残基。从我们的分析中得出的假设是，许多伴侣分子对基本残基的偏倚是由球状结构的基本热力学和动力学约束引起的。这也表明基本残基和分子伴侣的共同进化使蛋白质世界的结构多样性得以扩展。