Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Oxford NIHR Biomedical Research Centre, Oxford, UK.
Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Oxford NIHR Biomedical Research Centre, Oxford, UK. Electronic address: https://twitter.com/@alistairp2011.
J Mol Biol. 2022 Jun 15;434(11):167567. doi: 10.1016/j.jmb.2022.167567. Epub 2022 Mar 29.
Exploring the functional effect of a non-synonymous coding variant at the protein level requires multiple pieces of information to be interpreted appropriately. This is particularly important when embarking on the study of a potentially pathogenic variant linked to a rare or monogenic disease. Whereas accurate protein stability predictions alone are generally informative, other effects, such as disruption of post-translational modifications or weakened ligand binding, may also contribute to the disease phenotype. Furthermore, consideration of nearby variants that are found in the healthy population may strengthen or refute a given mechanistic hypothesis. Whilst there are several bioinformatics tools available that score a genetic variant in terms of deleteriousness, there is no single tool that assembles multiple effects of a variant on the encoded protein, beyond structural stability, and presents them on the structure for inspection. Venus is a web application which, given a protein substitution, rapidly estimates the predicted effect on protein stability of the variant, flags if the variant affects a post-translational modification site, a predicted linear motif or known annotation, and determines the effect on protein stability of variants which affect nearby residues and have been identified in healthy populations. Venus is built upon Michelanglo and the results can be exported to it, allowing them to be annotated and shared with other researchers. Venus is freely accessible at https://venus.cmd.ox.ac.uk and its source code is openly available at https://github.com/CMD-Oxford/Michelanglo-and-Venus.
探索蛋白质水平上非同义编码变异的功能效应需要适当解释多方面的信息。当开始研究与罕见或单基因疾病相关的潜在致病变异时，这一点尤为重要。虽然准确的蛋白质稳定性预测通常具有信息性，但其他效应，如翻译后修饰的破坏或配体结合能力减弱，也可能导致疾病表型。此外，考虑到健康人群中发现的附近变异可以加强或反驳特定的机制假说。虽然有几个生物信息学工具可以根据有害性对遗传变异进行评分，但没有一个工具可以综合变异对编码蛋白的多种效应，除了结构稳定性，并在结构上进行检查。金星是一个网络应用程序，给定一个蛋白质替换，它可以快速估计变异对蛋白质稳定性的预测影响，如果变异影响翻译后修饰位点、预测的线性基序或已知注释，则会标记出来，并确定影响附近残基的变异的蛋白质稳定性效应，这些变异已在健康人群中被识别。金星建立在 Michelanglo 之上，其结果可以导出到 Michelanglo 中，以便对其进行注释并与其他研究人员共享。金星可在 https://venus.cmd.ox.ac.uk 免费访问，其源代码可在 https://github.com/CMD-Oxford/Michelanglo-and-Venus 上公开获取。
