title: Allosteric regulation of Arf GTPases and their GEFs at the membrane interface.
abstract: Arf GTPases assemble protein complexes on membranes to carry out major functions in cellular traffic. An essential step is their activation by guanine nucleotide exchange factors (GEFs), whose Sec7 domain stimulates GDP/GTP exchange. ArfGEFs form 2 major families: ArfGEFs with DCB, HUS and HDS domains (GBF1 and BIG1/BIG2 in humans), which act at the Golgi; and ArfGEFs with a C-terminal PH domain (cytohesin, EFA6 and BRAG), which function at the plasma membrane and endosomes. In addition, pathogenic bacteria encode an ArfGEF with a unique membrane-binding domain. Here we review the allosteric regulation of Arf GTPases and their GEFs at the membrane interface. Membranes contribute several regulatory layers: at the GTPase level, where activation by GTP is coupled to membrane recruitment by a built-in structural device; at the Sec7 domain, which manipulates this device to ensure that Arf-GTP is attached to membranes; and at the level of non-catalytic ArfGEF domains, which form direct or GTPase-mediated interactions with membranes that enable a spectacular diversity of regulatory regimes. Notably, we show here that membranes increase the efficiency of a large ArfGEF (human BIG1) by 32-fold by interacting directly with its N-terminal DCB and HUS domains. The diversity of allosteric regulatory regimes suggests that ArfGEFs can function in cascades and circuits to modulate the shape, amplitude and duration of Arf signals in cells. Because Arf-like GTPases feature autoinhibitory elements similar to those of Arf GTPases, we propose that their activation also requires allosteric interactions of these elements with membranes or other proteins.
authors.affiliation: a Laboratoire de Biologie et Pharmacologie Appliquée, CNRS, Ecole Normale Supérieure de Cachan and Université Paris-Saclay , Cachan , France.
authors.forename: Agata
authors.initials: A
authors.lastname: Nawrotek
authors.affiliation: a Laboratoire de Biologie et Pharmacologie Appliquée, CNRS, Ecole Normale Supérieure de Cachan and Université Paris-Saclay , Cachan , France.
authors.forename: Mahel
authors.initials: M
authors.lastname: Zeghouf
authors.affiliation: a Laboratoire de Biologie et Pharmacologie Appliquée, CNRS, Ecole Normale Supérieure de Cachan and Université Paris-Saclay , Cachan , France.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cherfils
mesh_terms: D020727:ADP-Ribosylation Factors / Q000737:chemistry / Q000378:metabolism*; D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D020727:ADP-Ribosylation Factors
keywords: Arf; allostery; guanine nucleotide exchange factors; membrane; small GTPase; structure