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首页> 外文期刊>Journal of Molecular Biology >The Relationship Between Conservation, Thermodynamic Stability, and Function in the SH3 Domain Hydrophobic Core.
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The Relationship Between Conservation, Thermodynamic Stability, and Function in the SH3 Domain Hydrophobic Core.

机译：SH3域疏水核中保守性，热力学稳定性和功能之间的关系。

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摘要

To investigate the relationships between sequence conservation, protein stability, and protein function, we have measured the thermodynamic stability, folding kinetics, and in vitro peptide-binding activity of a large number of single-site substitutions in the hydrophobic core of the Fyn SH3 domain. Comparison of these data to that derived from an analysis of a large alignment of SH3 domain sequences revealed a very good correlation between the distinct pattern of conservation observed at each core position and the thermodynamic stability of mutants. Conservation was also found to correlate well with the unfolding rates of mutants, but not to the folding rates, suggesting that evolution selects more strongly for optimal native state packing interactions than for maximal folding rates. Structural analysis suggests that residue-residue core packing interactions are very similar in all SH3 domains, which provides an explanation for the correlation between conservation and mutant stability effects studied in a single SH3 domain. We also demonstrate a correlation between stability and the in vivo activity of mutants, and between conservation and activity. However, the relationship between conservation and activity was very strong only for the three most conserved hydrophobic core positions. The weaker correlation between activity and conservation seen at the other seven core positions indicates that maintenance of protein stability is the dominant selective pressure at these positions. In general, the pattern of conservation at hydrophobic core positions appears to arise from conserved packing constraints, and can be effectively utilized to predict the destabilizing effects of amino acid substitutions.
机译：为了研究序列保守性，蛋白质稳定性和蛋白质功能之间的关系，我们测量了Fyn SH3结构域疏水核心中大量单点取代的热力学稳定性，折叠动力学和体外肽结合活性。将这些数据与对SH3结构域序列的大序列比对分析得出的数据进行比较，发现在每个核心位置观察到的不同保守模式与突变体的热力学稳定性之间具有很好的相关性。还发现保守性与突变体的解折叠速率很好地相关，但是与折叠速率没有很好的相关性，这表明进化对最佳天然状态包装相互作用的选择比对最大折叠速率的选择更为强烈。结构分析表明，残基-残基核心堆积相互作用在所有SH3域中都非常相似，这为在单个SH3域中研究的保守性和突变体稳定性效应之间的相关性提供了解释。我们还证明了突变体的稳定性和体内活性之间以及保守性和活性之间的相关性。但是，仅对于三个最保守的疏水核心位置，保守性与活性之间的关系非常强。在其他七个核心位置看到的活性和保守性之间的相关性较弱，这表明维持蛋白质稳定性是这些位置的主要选择压力。通常，疏水核心位置的保守性模式似乎是由保守的堆积约束引起的，可以有效地用于预测氨基酸取代的去稳定作用。

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