title: The yeast p5 type ATPase, spf1, regulates manganese transport into the endoplasmic reticulum.
abstract: The endoplasmic reticulum (ER) is a large, multifunctional and essential organelle. Despite intense research, the function of more than a third of ER proteins remains unknown even in the well-studied model organism Saccharomyces cerevisiae. One such protein is Spf1, which is a highly conserved, ER localized, putative P-type ATPase. Deletion of SPF1 causes a wide variety of phenotypes including severe ER stress suggesting that this protein is essential for the normal function of the ER. The closest homologue of Spf1 is the vacuolar P-type ATPase Ypk9 that influences Mn(2+) homeostasis. However in vitro reconstitution assays with Spf1 have not yielded insight into its transport specificity. Here we took an in vivo approach to detect the direct and indirect effects of deleting SPF1. We found a specific reduction in the luminal concentration of Mn(2+) in ∆spf1 cells and an increase following it's overexpression. In agreement with the observed loss of luminal Mn(2+) we could observe concurrent reduction in many Mn(2+)-related process in the ER lumen. Conversely, cytosolic Mn(2+)-dependent processes were increased. Together, these data support a role for Spf1p in Mn(2+) transport in the cell. We also demonstrate that the human sequence homologue, ATP13A1, is a functionally conserved orthologue. Since ATP13A1 is highly expressed in developing neuronal tissues and in the brain, this should help in the study of Mn(2+)-dependent neurological disorders.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yifat
authors.initials: Y
authors.lastname: Cohen
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel ; Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Márton
authors.initials: M
authors.lastname: Megyeri
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: Oscar C W
authors.initials: OC
authors.lastname: Chen
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Condomitti
authors.affiliation: Department of Biochemistry, University of Geneva, Geneva, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Riezman
authors.affiliation: Department of Biochemistry, University of Geneva, Geneva, Switzerland.
authors.forename: Ursula
authors.initials: U
authors.lastname: Loizides-Mangold
authors.affiliation: School of Life Sciences, University of Sussex, Brighton, United Kingdom.
authors.forename: Alaa
authors.initials: A
authors.lastname: Abdul-Sada
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Nitzan
authors.initials: N
authors.lastname: Rimon
authors.affiliation: Department of Biochemistry, University of Geneva, Geneva, Switzerland ; National Centre of Competence in Research (NCCR) Chemical Biology, University of Geneva, Geneva, Switzerland.
authors.forename: Howard
authors.initials: H
authors.lastname: Riezman
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, United Kingdom.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel ; The Joseph Meyerhoff Professor of Biochemistry at the Weizmann Institute of Science, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Schuldiner
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D001692:Biological Transport; D018797:Cell Cycle Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D008345:Manganese / Q000378:metabolism*; D008861:Microsomes / Q000378:metabolism; D009154:Mutation; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D018528:ATP-Binding Cassette Transporters; D018797:Cell Cycle Proteins; C406793:SPF1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D008345:Manganese; D000251:Adenosine Triphosphatases