Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada.
Front Endocrinol (Lausanne). 2021 Jul 12;12:700066. doi: 10.3389/fendo.2021.700066. eCollection 2021.
The mammalian proglucagon gene () encodes three glucagon like sequences, glucagon, glucagon-like peptide-1 (GLP-1), and glucagon-like peptide-2 that are of similar length and share sequence similarity, with these hormones having cell surface receptors, glucagon receptor (Gcgr), GLP-1 receptor (Glp1r), and GLP-2 receptor (Glp2r), respectively. Gcgr, Glp1r, and Glp2r are all class B1 G protein-coupled receptors (GPCRs). Despite their sequence and structural similarity, analyses of sequences from rodents have found differences in patterns of sequence conservation and evolution. To determine whether these were rodent-specific traits or general features of these genes in mammals I analyzed coding and protein sequences for proglucagon and the receptors for proglucagon-derived peptides from the genomes of 168 mammalian species. Single copy genes for each gene were found in almost all genomes. In addition to glucagon sequences within Hystricognath rodents (e.g., guinea pig), glucagon sequences from a few other groups (e.g., pangolins and some bats) as well as changes in the proteolytic processing of GLP-1 in some bats are suggested to have functional effects. GLP-2 sequences display increased variability but accepted few substitutions that are predicted to have functional consequences. In parallel, Glp2r sequences display the most rapid protein sequence evolution, and show greater variability in amino acids at sites involved in ligand interaction, however most were not predicted to have a functional consequence. These observations suggest that a greater diversity in biological functions for proglucagon-derived peptides might exist in mammals.
哺乳动物的前胰高血糖素基因 () 编码三种胰高血糖素样序列,即胰高血糖素、胰高血糖素样肽-1 (GLP-1) 和胰高血糖素样肽-2,它们的长度相似,具有序列相似性,这些激素都有细胞表面受体,即胰高血糖素受体 (Gcgr)、GLP-1 受体 (Glp1r) 和 GLP-2 受体 (Glp2r)。Gcgr、Glp1r 和 Glp2r 均属于 B1 类 G 蛋白偶联受体 (GPCR)。尽管它们的序列和结构相似,但对啮齿动物序列的分析发现,它们的序列保守和进化模式存在差异。为了确定这些差异是啮齿动物特有的特征还是这些基因在哺乳动物中的一般特征,我分析了来自 168 种哺乳动物基因组的前胰高血糖素基因和前胰高血糖素衍生肽受体的编码和蛋白质序列。几乎所有基因组中都发现了每个基因的单拷贝基因。除了 Hystricognath 啮齿动物(如豚鼠)中的胰高血糖素序列外,一些其他类群(如穿山甲和一些蝙蝠)中的胰高血糖素序列以及一些蝙蝠中 GLP-1 的蛋白水解加工变化被认为具有功能效应。GLP-2 序列显示出更高的可变性,但接受了一些预测具有功能后果的替换。与此平行,Glp2r 序列显示出最快的蛋白质序列进化,并且在参与配体相互作用的氨基酸位点显示出更大的变异性,然而,大多数预测没有功能后果。这些观察结果表明,前胰高血糖素衍生肽在哺乳动物中可能具有更多样化的生物学功能。