title: The cytohesin coiled-coil domain interacts with threonine 276 to control membrane association.
abstract: Cell migration is regulated by a number of small GTPases, including members of the Arf family. Cytohesins, a family of Arf-activating proteins, have been extensively implicated in the regulation of Arfs during migration and cell shape change. Membrane association of both the Arf and its activating protein is a prerequisite for Arf activation. Therefore regulating the extent of cytohesin membrane association is a mechanism for controlling the initiation of cell movement. We have discovered a novel intramolecular interaction that controls the association of cytohesins with membranes. The presence of the coiled-coil domain reduces the association of cytohesin 2 with membranes. We demonstrate that this domain interacts with more C-terminal regions of the protein. This interaction is independent of another previously identified autoinhibitory conformation. A threonine residue (T276) in the cytohesin 2 PH domain is a target for phosphorylation by Akt. Mutation of this threonine to aspartic acid, to mimic phosphorylation, disrupts the binding of the coiled-coil domain to c-terminal regions and promotes membrane association of cytohesin 2. The presence of a second autoinhibitory interaction in the cytohesins suggests that these proteins can act a signal integrators that stimulate migration only after receive multiple pro-migratory signals.
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, United States of America.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Hiester
authors.forename: Lorraine C
authors.initials: LC
authors.lastname: Santy
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013912:Threonine / Q000378:metabolism*
chemical_list: D020690:GTPase-Activating Proteins; C102474:cytohesin-2; D013912:Threonine; D051057:Proto-Oncogene Proteins c-akt