title: Regulation of HMG-CoA reductase degradation requires the P-type ATPase Cod1p/Spf1p.
abstract: The integral ER membrane protein HMG-CoA reductase (HMGR) is a key enzyme of the mevalonate pathway from which sterols and other essential molecules are produced. HMGR degradation occurs in the ER and is regulated by mevalonate-derived signals. Little is known about the mechanisms responsible for regulating HMGR degradation. The yeast Hmg2p isozyme of HMGR undergoes regulated degradation in a manner very similar to mammalian HMGR, allowing us to isolate mutants deficient in regulating Hmg2p stability. We call these mutants cod mutants for the control of HMG-CoA reductase degradation. With this screen, we have identified the first gene of this class, COD1, which encodes a P-type ATPase and is identical to SPF1. Our data suggested that Cod1p is a calcium transporter required for regulating Hmg2p degradation. This role for Cod1p is distinctly different from that of the well-characterized Ca(2+) P-type ATPase Pmr1p which is neither required for Hmg2p degradation nor its control. The identification of Cod1p is especially intriguing in light of the role Ca(2+) plays in the regulated degradation of mammalian HMGR.
authors.affiliation: Department of Biology, University of California San Diego, La Jolla, California 92093-0347, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Cronin
authors.forename: A
authors.initials: A
authors.lastname: Khoury
authors.forename: D K
authors.initials: DK
authors.lastname: Ferry
authors.forename: R Y
authors.initials: RY
authors.lastname: Hampton
mesh_terms: D018528:ATP-Binding Cassette Transporters; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004533:Egtazic Acid / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004795:Enzyme Stability / Q000187:drug effects / Q000235:genetics; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D016296:Mutagenesis; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D011500:Protein Synthesis Inhibitors; C406793:SPF1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014452:Ubiquitins; D004533:Egtazic Acid; D006903:Hydroxymethylglutaryl CoA Reductases; D000251:Adenosine Triphosphatases; D002118:Calcium