title: Manganese toxicity and Saccharomyces cerevisiae Mam3p, a member of the ACDP (ancient conserved domain protein) family.
abstract: Manganese is an essential, but potentially toxic, trace metal in biological systems. Overexposure to manganese is known to cause neurological deficits in humans, but the pathways that lead to manganese toxicity are largely unknown. We have employed the bakers' yeast Saccharomyces cerevisiae as a model system to identify genes that contribute to manganese-related damage. In a genetic screen for yeast manganese-resistance mutants, we identified S. cerevisiae MAM3 as a gene which, when deleted, would increase cellular tolerance to toxic levels of manganese and also increased the cell's resistance towards cobalt and zinc. By sequence analysis, Mam3p shares strong similarity with the mammalian ACDP (ancient conserved domain protein) family of polypeptides. Mutations in human ACDP1 have been associated with urofacial (Ochoa) syndrome. However, the functions of eukaryotic ACDPs remain unknown. We show here that S. cerevisiae MAM3 encodes an integral membrane protein of the yeast vacuole whose expression levels directly correlate with the degree of manganese toxicity. Surprisingly, Mam3p contributes to manganese toxicity without any obvious changes in vacuolar accumulation of metals. Furthermore, through genetic epistasis studies, we demonstrate that MAM3 operates independently of the well-established manganese-trafficking pathways in yeast, involving the manganese transporters Pmr1p, Smf2p and Pho84p. This is the first report of a eukaryotic ACDP family protein involved in metal homoeostasis.
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Yang
authors.forename: Laran T
authors.initials: LT
authors.lastname: Jensen
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Gardner
authors.forename: Valeria C
authors.initials: VC
authors.lastname: Culotta
mesh_terms: D000595:Amino Acid Sequence; D001692:Biological Transport; D003035:Cobalt / Q000378:metabolism / Q000494:pharmacology; D017124:Conserved Sequence; D025141:Drug Resistance, Fungal / Q000235:genetics; D004843:Epistasis, Genetic; D018628:Gene Dosage; D006706:Homeostasis; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008345:Manganese / Q000378:metabolism / Q000494:pharmacology*; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000502:physiology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014617:Vacuoles / Q000378:metabolism; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology
chemical_list: C502968:Mam3 protein, S cerevisiae; D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; D003035:Cobalt; D008345:Manganese; D015032:Zinc