Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294.
Department of Biology, Williams College, Williamstown, MA 01267.
Mol Biol Cell. 2019 May 15;30(11):1249-1271. doi: 10.1091/mbc.E18-12-0820.
Detailed structural, biochemical, cell biological, and genetic studies of any gene/protein are required to develop models of its actions in cells. Studying a protein family in the aggregate yields additional information, as one can include analyses of their coevolution, acquisition or loss of functionalities, structural pliability, and the emergence of shared or variations in molecular mechanisms. An even richer understanding of cell biology can be achieved through evaluating functionally linked protein families. In this review, we summarize current knowledge of protein families: the ARF GTPases, the guanine nucleotide exchange factors (ARF GEFs) that activate them, and the GTPase-activating proteins (ARF GAPs) that have the ability to both propagate and terminate signaling. However, despite decades of scrutiny, our understanding of how these essential proteins function in cells remains fragmentary. We believe that the inherent complexity of ARF signaling and its regulation by GEFs and GAPs will require the concerted effort of many laboratories working together, ideally within a consortium to optimally pool information and resources. The collaborative study of these three functionally connected families (≥70 mammalian genes) will yield transformative insights into regulation of cell signaling.
需要对任何基因/蛋白质进行详细的结构、生化、细胞生物学和遗传研究，以建立其在细胞中作用的模型。综合研究蛋白质家族可以提供更多信息，因为可以包括对它们的共同进化、功能获得或丧失、结构柔韧性以及分子机制的共享或变化的分析。通过评估功能相关的蛋白质家族，可以更深入地了解细胞生物学。在这篇综述中，我们总结了 ARF GTPases、激活它们的鸟嘌呤核苷酸交换因子（ARF GEFs）以及具有传播和终止信号能力的 GTPase 激活蛋白（ARF GAPs）等蛋白质家族的现有知识。然而，尽管经过几十年的研究，我们对这些必需蛋白质在细胞中如何发挥作用的理解仍然很零碎。我们相信，ARF 信号转导的固有复杂性及其由 GEFs 和 GAPs 调节，将需要许多实验室共同努力，理想情况下在一个联盟内共同努力，以最佳地汇集信息和资源。对这三个功能相关的家族（≥70 个哺乳动物基因）进行协作研究，将为细胞信号转导的调控带来变革性的见解。
