Origin and Isoform Specific Functions of Exchange Proteins Directly Activated by cAMP: A Phylogenetic Analysis.
Origin and Isoform Specific Functions of Exchange Proteins Directly Activated by cAMP: A Phylogenetic Analysis.
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DOI：
10.3390/cells10102750
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发表时间：
2021-10-14
期刊：
影响因子：
6
通讯作者：
Cheng X
中科院分区：
文献类型：
--
作者：
Ni Z;Cheng X
由cAMP直接激活的交换蛋白(EPAC1和Epac2)是典型的第二信使cAMP的几个细胞效应物家族之一。为了了解EPAC蛋白的起源和分子进化，我们对EPAC1和Epac2进行了全面的系统发育分析。我们的研究表明，与其表亲PKA不同，EPAC蛋白只存在于多细胞后生动物中。在EPAC家族中，EPAC1只与脊索动物有关，而Epac2则横跨整个动物界。尽管EPAC1的起源更现代，但EPAC1蛋白在物种之间显示出更多的序列多样性，这表明EPAC1经历了更多的选择，进化速度也比Epac2快。对EPACs的cAMP结合结构域(CBD)和鸟嘌呤核苷酸交换结构域(Gef)的系统发育分析进一步表明，EPAC1和Epac2在较大的环核苷酸受体和RAPgef家族中紧密聚集在一起。这些结果支持这样的观点，即EPAC1和Epac2共享一个共同的祖先，这是PKA的CBD和来自RAPGEF1的环境基金之间的融合产生的。另一方面，两个末端和RAS关联(RA)结构域在两种异构体之间显示出最大的序列多样性。这些区域内的序列多样性对EPAC的异构体特异性功能有很大贡献。重要的是，在RA结构域中已经确定了独特的异构体特异性序列基序。
Exchange proteins directly activated by cAMP (EPAC1 and EPAC2) are one of the several families of cellular effectors of the prototypical second messenger cAMP. To understand the origin and molecular evolution of EPAC proteins, we performed a comprehensive phylogenetic analysis of EPAC1 and EPAC2. Our study demonstrates that unlike its cousin PKA, EPAC proteins are only present in multicellular Metazoa. Within the EPAC family, EPAC1 is only associated with chordates, while EPAC2 spans the entire animal kingdom. Despite a much more contemporary origin, EPAC1 proteins show much more sequence diversity among species, suggesting that EPAC1 has undergone more selection and evolved faster than EPAC2. Phylogenetic analyses of the individual cAMP binding domain (CBD) and guanine nucleotide exchange (GEF) domain of EPACs, two most conserved regions between the two isoforms, further reveal that EPAC1 and EPAC2 are closely clustered together within both the larger cyclic nucleotide receptor and RAPGEF families. These results support the notion that EPAC1 and EPAC2 share a common ancestor resulting from a fusion between the CBD of PKA and the GEF from RAPGEF1. On the other hand, the two terminal extremities and the RAS-association (RA) domains show the most sequence diversity between the two isoforms. Sequence diversities within these regions contribute significantly to the isoform-specific functions of EPACs. Importantly, unique isoform-specific sequence motifs within the RA domain have been identified.
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影响因子：
29
作者：
Fukuda M;Williams KW;Gautron L;Elmquist JK
通讯作者：
Elmquist JK
影响因子：
7.7
作者：
Alenkvist, Ida;Gandasi, Nikhil R.;Tengholm, Anders
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Tengholm, Anders
DOI：
10.1073/pnas.2001045117
发表时间：
2020-04-07
影响因子：
11.1
作者：
Evans, Scott D.;Hughes, Ian V.;Droser, Mary L.
通讯作者：
Droser, Mary L.
影响因子：
1.7
作者：
Desper, R;Gascuel, O
通讯作者：
Gascuel, O
树突镜：大型系统发育树的互动观众。
影响因子：
3
作者：
Huson, Daniel H.;Richter, Daniel C.;Rausch, Christian;Dezulian, Tobias;Franz, Markus;Rupp, Regula
通讯作者：
Rupp, Regula