Conservation and divergence of protein pathways in the vertebrate heart
Conservation and divergence of protein pathways in the vertebrate heart
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DOI：
10.1371/journal.pbio.3000437
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发表时间：
2019-09-01
期刊：
影响因子：
9.8
通讯作者：
Conlon, Frank L.
中科院分区：
文献类型：
--
作者：
Federspiel, Joel D.;Tandon, Panna;Conlon, Frank L.
心脏病是西方世界的主要死因。对人类心脏发育和内稳态以及相关疾病状态的分子基础的机械理解依赖于动物模型的使用。在这里，我们介绍了4种具有双循环系统的模式脊椎动物的心脏蛋白质组：猪(Sus Scrofa)、小鼠(Mus Musculus)和2只青蛙(非洲爪哇和热带非洲爪蛙)。确定哪些蛋白质和蛋白质途径是保守的，哪些在这些物种中存在分歧，这将有助于我们选择适当的模型来确定蛋白质功能和模拟人类疾病。我们发现了哺乳动物和两栖动物特有的，以及物种特有的，丰富的蛋白质和蛋白质途径。其中，我们发现并验证了非洲爪哇体内细胞周期相关蛋白的丰富。为了进一步研究心脏蛋白质组中的功能单位，我们开发了一种计算方法来描述跨物种的蛋白质复合体的丰度。最后，我们通过测试Kielin/Chordin-like Protein(KCP)的作用，证明了这些数据集对于预测研究特定心脏疾病的合适模型系统的有效性。KCP是一种在青蛙心脏中发现的蛋白质，与哺乳动物相比，这种蛋白质在青蛙心脏中含量较高。我们确定，非洲爪哇KCP基因的胚系突变会导致瓣膜缺陷，最终导致心力衰竭和死亡。因此，将这些发现与导致心脏疾病的蛋白质的数据结合起来，应该会导致对蛋白质功能和疾病状态的改进的、特定物种的模型的开发。
Heart disease is the leading cause of death in the western world. Attaining a mechanistic understanding of human heart development and homeostasis and the molecular basis of associated disease states relies on the use of animal models. Here, we present the cardiac proteomes of 4 model vertebrates with dual circulatory systems: the pig (Sus scrofa), the mouse (Mus musculus), and 2 frogs (Xenopus laevis and Xenopus tropicalis). Determination of which proteins and protein pathways are conserved and which have diverged within these species will aid in our ability to choose the appropriate models for determining protein function and to model human disease. We uncover mammalian- and amphibian-specific, as well as species-specific, enriched proteins and protein pathways. Among these, we find and validate an enrichment in cell-cycle-associated proteins within Xenopus laevis. To further investigate functional units within cardiac proteomes, we develop a computational approach to profile the abundance of protein complexes across species. Finally, we demonstrate the utility of these data sets for predicting appropriate model systems for studying given cardiac conditions by testing the role of Kielin/chordin-like protein (Kcp), a protein found as enriched in frog hearts compared to mammals. We establish that germ-line mutations in Kcp in Xenopus lead to valve defects and, ultimately, cardiac failure and death. Thus, integrating these findings with data on proteins responsible for cardiac disease should lead to the development of refined, species-specific models for protein function and disease states.