ARF GTPases and their GEFs and GAPs: concepts and challenges

• Type of Material: Article
• Authors: Elizabeth Sztul, University of Alabama Birmingham; Pei-Wen Chen, Williams College; James E. Casanova, University of Virginia; Jacqueline Cherfils, CNRS and Ecole Normale Supérieure Paris-Saclay; Joel B. Decks, University of Alberta; David G. Lambright, University of Massachusetts; Fang-Jen S. Lee, National Taiwan University; Paul A. Randazzo, National Cancer Institute; Lorraine C. Santy, Pennsylvania State University; Annette Schuermann, German Institute of Human Nutrition; Ilka Wilhelmi, German Institute of Human Nutrition; Marielle E. Yohe, National Cancer Institute; Richard A Kahn, Emory University
• Language: English
• Date: 2019-05-15
• Publisher: American Society for Cell Biology
• Publication Version: Final Published Version
• Copyright Statement: German Institute of Human Nutrition
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1091/mbc.E18-12-0820
• Title of Journal or Parent Work: Molecular Biology of the Cell
• ISSN: 1059-1524
• Volume: 30
• Issue: 11
• Start Page: 1249
• End Page: 1271
• Grant/Funding Information: J.B.D. is the Canada Research Chair (Tier II) in Evolutionary Cell Biology.; This work was supported by grants from the NIH (R35GM122568 to R.A.K., R01DK093729 to L.C.S., R01GM127361 to J.E.C., R01GM122802 to E.S., R01GM056324 to D.G.L.); the National Science Foundation (MCB-1615607 to E.S.); the German Research Foundation DFG (SFB 958 to I.W. and A.S.); the National Health Research Institutes (NHRI) in Taiwan (NHRI-EX106-10601B1 to F.-J.S.L.); the NIH Intramural Program (project BC 007365 to P.A.R. and BC011805 to M.E.Y.); Alex’s Lemonade Stand Foundation Young Investigator Award (M.E.Y.); the Institut National du Cancer (INCa, grant number 2014-160 to J.C.); and the Fondation pour la Recherche Médicale (FRM, grant number DEQ20150331694 to J.C.).
• Keywords: GUANINE-NUCLEOTIDE-EXCHANGE; GRIP DOMAIN PROTEINS; ADP-RIBOSYLATION FACTOR; BREFELDIN-A; Cell Biology; ACTIVATING-PROTEIN; STRUCTURAL BASIS; GTP-BINDING PROTEINS; SMALL G-PROTEINS; Science & Technology; TRANS-GOLGI NETWORK; AP-3 ADAPTER COMPLEX; Life Sciences & Biomedicine
• Research Categories: Chemistry, Biochemistry; Biology, Cell

Abstract

German Institute of Human Nutrition 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 three 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.