title: Golgi anti-apoptotic proteins are highly conserved ion channels that affect apoptosis and cell migration.
abstract: Golgi anti-apoptotic proteins (GAAPs) are multitransmembrane proteins that are expressed in the Golgi apparatus and are able to homo-oligomerize. They are highly conserved throughout eukaryotes and are present in some prokaryotes and orthopoxviruses. Within eukaryotes, GAAPs regulate the Ca(2+) content of intracellular stores, inhibit apoptosis, and promote cell adhesion and migration. Data presented here demonstrate that purified viral GAAPs (vGAAPs) and human Bax inhibitor 1 form ion channels and that vGAAP from camelpox virus is selective for cations. Mutagenesis of vGAAP, including some residues conserved in the recently solved structure of a related bacterial protein, BsYetJ, altered the conductance (E207Q and D219N) and ion selectivity (E207Q) of the channel. Mutation of residue Glu-207 or -178 reduced the effects of GAAP on cell migration and adhesion without affecting protection from apoptosis. In contrast, mutation of Asp-219 abrogated the anti-apoptotic activity of GAAP but not its effects on cell migration and adhesion. These results demonstrate that GAAPs are ion channels and define residues that contribute to the ion-conducting pore and affect apoptosis, cell adhesion, and migration independently.
authors.affiliation: From the Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
authors.forename: Guia
authors.initials: G
authors.lastname: Carrara
authors.affiliation: From the Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
authors.forename: Nuno
authors.initials: N
authors.lastname: Saraiva
authors.affiliation: the Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, United Kingdom.
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
authors.affiliation: the Division of Molecular Biosciences, Imperial College London, London SW7 2AZ, United Kingdom, and.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Byrne
authors.affiliation: the Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom, dp350@cam.ac.uk.
authors.forename: David L
authors.initials: DL
authors.lastname: Prole
authors.affiliation: the Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom, cwt1000@cam.ac.uk.
authors.forename: Colin W
authors.initials: CW
authors.lastname: Taylor
authors.affiliation: From the Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom, gls37@cam.ac.uk.
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Smith
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002465:Cell Movement; D017124:Conserved Sequence; D006801:Humans; D007473:Ion Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D016062:Porosity; D011487:Protein Conformation
chemical_list: D007473:Ion Channels
keywords: Electrophysiology; Ion Channel; Lipid Bilayer; Membrane Protein; Viral Protein