Genetic basis of functional variability in adhesion G protein-coupled receptors
Genetic basis of functional variability in adhesion G protein-coupled receptors
复制标题
DOI：
10.1038/s41598-019-46265-x
复制
发表时间：
2019-07-30
影响因子：
4.6
通讯作者：
Schoeneberg, Torsten
中科院分区：
文献类型：
--
作者：
Knierim, Alexander Bernd;Roethe, Juliane;Schoeneberg, Torsten
粘附G蛋白偶联受体（aGPCR）的巨大尺寸与复杂的基因组外显子-内含子结构一起沿着，产生多种mRNA变体。需要aGPCR变体的综合目录，以适当评估在结构、体外和动物模型研究中发现的aGPCR的复杂功能。我们使用一个已建立的生物信息学管道从深度测序的转录组中提取、量化和可视化aGPCR的mRNA变体。数据分析表明，aGPCR具有多个转录起始位点，甚至在内含子内，并且组织特异性剪接是频繁的。平均而言，19个显著表达的转录物变体源自给定的aGPCR基因。由转录物变体编码的N末端的结构域结构通常不同，并且不具有或具有不完整的七螺旋跨膜锚的N末端以及分开的七螺旋跨膜结构域通常源自aGPCR基因。对选定的aGPCR转录变体的实验分析揭示了显著的功能差异。我们的分析有一个合理的设计的aGPCR结构的结构分析和基因缺陷的小鼠品系的影响，并提供了新的支持，两个独立的功能，大N端和跨膜结构域的aGPCR。
The enormous sizes of adhesion G protein-coupled receptors (aGPCRs) go along with complex genomic exon-intron architectures giving rise to multiple mRNA variants. There is a need for a comprehensive catalog of aGPCR variants for proper evaluation of the complex functions of aGPCRs found in structural, in vitro and animal model studies. We used an established bioinformatics pipeline to extract, quantify and visualize mRNA variants of aGPCRs from deeply sequenced transcriptomes. Data analysis showed that aGPCRs have multiple transcription start sites even within introns and that tissue-specific splicing is frequent. On average, 19 significantly expressed transcript variants are derived from a given aGPCR gene. The domain architecture of the N terminus encoded by transcript variants often differs and N termini without or with an incomplete seven-helix transmembrane anchor as well as separate seven-helix transmembrane domains are frequently derived from aGPCR genes. Experimental analyses of selected aGPCR transcript variants revealed marked functional differences. Our analysis has an impact on a rational design of aGPCR constructs for structural analyses and gene-deficient mouse lines and provides new support for independent functions of both, the large N terminus and the transmembrane domain of aGPCRs.