Can Predicted Protein 3D Structures Provide Reliable Insights into whether Missense Variants Are Disease Associated?
Can Predicted Protein 3D Structures Provide Reliable Insights into whether Missense Variants Are Disease Associated?
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DOI：
10.1016/j.jmb.2019.04.009
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发表时间：
2019-05-17
影响因子：
5.6
通讯作者：
Sternberg, Michael J. E.
中科院分区：
文献类型：
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作者：
Ittisoponpisan, Sirawit;Islam, Suhail A.;Sternberg, Michael J. E.
蛋白质结构的知识可用于预测错义变体的表型结果。由于人类蛋白质组的结构覆盖率可以大致增加三倍，超过50%的残基，如果同源性预测的结构，包括除了实验确定的坐标，重要的是要评估使用预测模型的可靠性时，分析错义变体。因此，我们通过使用实验和预测的结构来评估错义变体是否具有结构破坏性。我们考虑了606个实验结构，并表明在分析的1965个疾病相关的错义变体中，有40%的突变体结构发生了结构性破坏性变化。在2134个中性变异体中，只有11%具有结构性破坏。重要的是，当使用Phyre2算法预测的1052个结构时，即使当模型共享低（
Knowledge of protein structure can be used to predict the phenotypic consequence of a missense variant. Since structural coverage of the human proteome can be roughly tripled to over 50% of the residues if homology-predicted structures are included in addition to experimentally determined coordinates, it is important to assess the reliability of using predicted models when analyzing missense variants. Accordingly, we assess whether a missense variant is structurally damaging by using experimental and predicted structures. We considered 606 experimental structures and show that 40% of the 1965 disease-associated missense variants analyzed have a structurally damaging change in the mutant structure. Only 11% of the 2134 neutral variants are structurally damaging. Importantly, similar results are obtained when 1052 structures predicted using Phyre2 algorithm were used, even when the model shares low (