Heterotrimeric G-proteins: a short history
Heterotrimeric G-proteins: a short history
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DOI：
10.1038/sj.bjp.0706405
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发表时间：
2006-01-01
影响因子：
7.3
通讯作者：
Kostenis, E
中科院分区：
文献类型：
--
作者：
Milligan, G;Kostenis, E
人类约有 865 个基因编码 G 蛋白偶联受体 (GPCR)。异三聚鸟嘌呤核苷酸结合蛋白（G 蛋白）的功能是将来自大量受体的信号转导至效应系统，包括改变细胞内第二信使的产生、释放或降解速率的离子通道和酶。然而，直到 20 世纪 70 年代，这种转导蛋白的存在才被认真地提出。细菌毒素的组合通过共价修饰某些 G 蛋白的 α 亚基来介导其作用，而突变细胞系由于无法表达或表达功能失调的 G 蛋白而无法响应激动剂而产生环 AMP，因此可以对其进行鉴定和纯化。在最初的克隆工作之后，同源克隆已将人类 G 蛋白定义为源自 35 个基因，其中 16 个编码 α 亚基、5 个 β 亚基和 14 个 γ 亚基。所有这些都起到鸟嘌呤核苷酸交换开关的作用，并且在机制上与酶 GTP 酶的其他蛋白质相似。虽然最初并没有被轻易接受，但现在已经确定β/γ复合物介导的功能至少与α亚基一样多。不同α亚基之间嵌合体的产生定义了一级/二级序列和晶体结构的不同部分的作用，并且具有相互作用蛋白质的共晶体使人们详细了解了它们的分子结构和功能基础。最后，对此类嵌合体的进一步修饰产生了一系列具有更大混杂性的 G 蛋白 α 亚基，可在 GPCR 类别之间相互作用，并开始在药物发现计划中使用此类修饰的 G 蛋白。
Some 865 genes in man encode G-protein-coupled receptors (GPCRs). The heterotrimeric guanine nucleotide-binding proteins (G-proteins) function to transduce signals from this vast panoply of receptors to effector systems including ion channels and enzymes that alter the rate of production, release or degradation of intracellular second messengers. However, it was not until the 1970s that the existence of such transducing proteins was even seriously suggested. Combinations of bacterial toxins that mediate their effects via covalent modification of the alpha-subunit of certain G-proteins and mutant cell lines that fail to generate cyclic AMP in response to agonists because they either fail to express or express a malfunctional G-protein allowed their identification and purification. Subsequent to initial cloning efforts, cloning by homology has defined the human G-proteins to derive from 35 genes, 16 encoding alpha-subunits, five beta and 14 gamma. All function as guanine nucleotide exchange on-off switches and are mechanistically similar to other proteins that are enzymic GTPases. Although not readily accepted initially, it is now well established that beta/gamma complexes mediate as least as many functions as the alpha-subunits. The generation of chimeras between different a-subunits defined the role of different sections of the primary/secondary sequence and crystal structures and cocrystals with interacting proteins have given detailed understanding of their molecular structure and basis of function. Finally, further modifications of such chimeras have generated a range of G-protein alpha-subunits with greater promiscuity to interact across GPCR classes and initiated the use of such modified G-proteins in drug discovery programmes.