Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Copenhagen, Denmark; Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Biophys J. 2023 Jun 6;122(11):2176-2191. doi: 10.1016/j.bpj.2022.12.031. Epub 2023 Jan 3.
Next-generation sequencing of human genomes reveals millions of missense variants, some of which may lead to loss of protein function and ultimately disease. Here, we investigate missense variants in membrane proteins-key drivers in cell signaling and recognition. We find enrichment of pathogenic variants in the transmembrane region across 19,000 functionally classified variants in human membrane proteins. To accurately predict variant consequences, one fundamentally needs to understand the underlying molecular processes. A key mechanism underlying pathogenicity in missense variants of soluble proteins has been shown to be loss of stability. Membrane proteins, however, are widely understudied. Here, we interpret variant effects on a larger scale by performing structure-based estimations of changes in thermodynamic stability using a membrane-specific energy function and analyses of sequence conservation during evolution of 15 transmembrane proteins. We find evidence for loss of stability being the cause of pathogenicity in more than half of the pathogenic variants, indicating that this is a driving factor also in membrane-protein-associated diseases. Our findings show how computational tools aid in gaining mechanistic insights into variant consequences for membrane proteins. To enable broader analyses of disease-related and population variants, we include variant mappings for the entire human proteome.
人类基因组的下一代测序揭示了数百万个错义变异，其中一些可能导致蛋白质功能丧失，最终导致疾病。在这里，我们研究了膜蛋白中的错义变异，这些蛋白是细胞信号转导和识别的关键驱动因素。我们发现，在人类膜蛋白中 19000 个功能分类的变异中，跨膜区域存在致病性变异的富集。为了准确预测变异的后果，人们从根本上需要了解潜在的分子过程。可溶性蛋白中错义变异的致病性的一个关键机制已经被证明是稳定性的丧失。然而，膜蛋白的研究还远远不够。在这里，我们通过使用膜特定的能量函数进行热力学稳定性变化的结构基础估计，以及对 15 种跨膜蛋白进化过程中的序列保守性进行分析，在更大的范围内解释了变异的影响。我们发现，稳定性丧失是超过一半致病性变异致病性的原因，这表明这也是膜蛋白相关疾病的一个驱动因素。我们的研究结果表明，计算工具如何帮助深入了解膜蛋白变异后果的机制。为了能够更广泛地分析与疾病相关的和人群中的变异，我们包括了整个人类蛋白质组的变异映射。
