| Manganese toxicity and Saccharomyces cerevisiae Mam3p, a member of the ACDP (ancient conserved domain protein) family. | |
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MedLine Citation:
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PMID: 15498024 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Mei Yang; Laran T Jensen; Allison J Gardner; Valeria C Culotta |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: The Biochemical journal Volume: 386 ISSN: 1470-8728 ISO Abbreviation: Biochem. J. Publication Date: 2005 Mar |
Date Detail:
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Created Date: 2005-03-03 Completed Date: 2005-08-25 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 2984726R Medline TA: Biochem J Country: England |
Other Details:
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Languages: eng Pagination: 479-87 Citation Subset: IM |
Affiliation:
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Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Biological Transport Cobalt / metabolism, pharmacology Conserved Sequence* Drug Resistance, Fungal / genetics Epistasis, Genetic Gene Dosage Homeostasis Humans Intracellular Membranes / metabolism Manganese / metabolism, pharmacology* Membrane Proteins / chemistry*, genetics, metabolism* Mitochondria / physiology Molecular Sequence Data Mutation / genetics Protein Structure, Tertiary Saccharomyces cerevisiae / cytology, drug effects*, genetics, metabolism* Saccharomyces cerevisiae Proteins / chemistry*, genetics, metabolism* Vacuoles / metabolism Zinc / metabolism, pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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ES 07141/ES/NIEHS NIH HHS; ES 08996/ES/NIEHS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Mam3 protein, S cerevisiae; 0/Membrane Proteins; 0/Saccharomyces cerevisiae Proteins; 7439-96-5/Manganese; 7440-48-4/Cobalt; 7440-66-6/Zinc |
| Comments/Corrections | |
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