Department of Integrative Biology & Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Texas Therapeutics Institute, Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Cells. 2021 Oct 14;10(10):2750. doi: 10.3390/cells10102750.
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.
环腺苷酸（cAMP）直接激活交换蛋白（EPAC1 和 EPAC2）是经典第二信使 cAMP 的几种细胞效应器家族之一。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，与它的表亲蛋白激酶 A（PKA）不同，EPAC 蛋白仅存在于多细胞后生动物中。在 EPAC 家族中，EPAC1 仅与脊索动物有关，而 EPAC2 则跨越整个动物界。尽管起源较晚，但 EPAC1 蛋白在物种间表现出更多的序列多样性，这表明 EPAC1 经历了更多的选择，进化速度比 EPAC2 更快。对 EPAC 两个最保守区域（即单个 cAMP 结合域（CBD）和鸟苷核苷酸交换（GEF）域）的系统发育分析进一步揭示，EPAC1 和 EPAC2 在较大的环核苷酸受体和 RAPGEF 家族内紧密聚集在一起。这些结果支持 EPAC1 和 EPAC2 具有共同祖先的观点，该祖先来自于 PKA 的 CBD 和 RAPGEF1 的 GEF 之间的融合。另一方面，两个末端和 RAS 相关（RA）结构域在两种同工型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 的同工型特异性功能有重要贡献。重要的是，在 RA 结构域内已经确定了独特的同工型特异性序列基序。
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