Melamud Eugene, Moult John
Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, 9600 Gudelsky Drive, Rockville, MD 20850, USA.
Nucleic Acids Res. 2009 Aug;37(14):4862-72. doi: 10.1093/nar/gkp444. Epub 2009 Jun 15.
Even though nearly every human gene has at least one alternative splice form, very little is so far known about the structure and function of resulting protein products. It is becoming increasingly clear that a significant fraction of all isoforms are products of noisy selection of splice sites and thus contribute little to actual functional diversity, and may potentially be deleterious. In this study, we examine the impact of alternative splicing on protein sequence and structure in three datasets: alternative splicing events conserved across multiple species, alternative splicing events in genes that are strongly linked to disease and all observed alternative splicing events. We find that the vast majority of all alternative isoforms result in unstable protein conformations. In contrast to that, the small subset of isoforms conserved across species tends to maintain protein structural integrity to a greater extent. Alternative splicing in disease-associated genes produces unstable structures just as frequently as all other genes, indicating that selection to reduce the effects of alternative splicing on this set is not especially pronounced. Overall, the properties of alternative spliced proteins are consistent with the outcome of noisy selection of splice sites by splicing machinery.
尽管几乎每个人类基因都至少有一种可变剪接形式，但迄今为止，对于由此产生的蛋白质产物的结构和功能却知之甚少。越来越明显的是，所有异构体中有很大一部分是剪接位点随机选择的产物，因此对实际功能多样性贡献不大，甚至可能具有潜在危害。在本研究中，我们在三个数据集中研究了可变剪接对蛋白质序列和结构的影响：多个物种中保守的可变剪接事件、与疾病密切相关的基因中的可变剪接事件以及所有观察到的可变剪接事件。我们发现，绝大多数可变异构体都会导致蛋白质构象不稳定。相比之下，跨物种保守的一小部分异构体往往能在更大程度上维持蛋白质结构的完整性。疾病相关基因中的可变剪接产生不稳定结构的频率与所有其他基因一样高，这表明减少可变剪接对这组基因影响的选择并不特别明显。总体而言，可变剪接蛋白质的特性与剪接机制对剪接位点随机选择的结果一致。
