Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors
Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors
复制标题
DOI：
10.1016/j.cell.2019.10.010
复制
发表时间：
2019-10-31
期刊：
影响因子：
64.5
通讯作者：
Gloriam, David E.
中科院分区：
文献类型：
--
作者：
Foster, Simon R.;Hauser, Alexander S.;Gloriam, David E.
肽能系统是人类最丰富的配体受体介导的信号网络。然而，许多多肽和超过100 G蛋白偶联受体（gpcr）的生理作用仍然难以捉摸。在这里，我们报告了同源肽和受体的配对。结合313个物种的比较基因组学和人类A类gpcr的所有蛋白质序列和结构的生物信息学，我们确定了揭示其他潜在肽能信号系统的普遍特征。通过三种正交生化试验，我们将17种内源性配体与5种与疾病相关的孤儿gpcr配对，包括遗传、肿瘤、神经和生殖系统疾病。我们还鉴定了具有公认配体和病理生理作用的九种受体的额外肽。这种综合计算和多方面的实验方法扩展了肽- gpcr网络，并为阐明这些信号系统在人类生理和疾病中的作用的研究开辟了道路。
The peptidergic system is the most abundant network of ligand-receptor-mediated signaling in humans. However, the physiological roles remain elusive for numerous peptides and more than 100 G protein-coupled receptors (GPCRs). Here we report the pairing of cognate peptides and receptors. Integrating comparative genomics across 313 species and bioinformatics on all protein sequences and structures of human class A GPCRs, we identify universal characteristics that uncover additional potential peptidergic signaling systems. Using three orthogonal biochemical assays, we pair 17 proposed endogenous ligands with five orphan GPCRs that are associated with diseases, including genetic, neoplastic, nervous and reproductive system disorders. We also identify additional peptides for nine receptors with recognized ligands and pathophysiological roles. This integrated computational and multifaceted experimental approach expands the peptide-GPCR network and opens the way for studies to elucidate the roles of these signaling systems in human physiology and disease.