title: Direct Comparison of Manganese Detoxification/Efflux Proteins and Molecular Characterization of ZnT10 Protein as a Manganese Transporter.
abstract: Manganese homeostasis involves coordinated regulation of specific proteins involved in manganese influx and efflux. However, the proteins that are involved in detoxification/efflux have not been completely resolved nor has the basis by which they select their metal substrate. Here, we compared six proteins, which were reported to be involved in manganese detoxification/efflux, by evaluating their ability to reduce manganese toxicity in chicken DT40 cells, finding that human ZnT10 (hZnT10) was the most significant contributor. A domain swapping and substitution analysis between hZnT10 and the zinc-specific transporter hZnT1 showed that residue Asn(43), which corresponds to the His residue constituting the potential intramembranous zinc coordination site in other ZnT transporters, is necessary to impart hZnT10's unique manganese mobilization activity; residues Cys(52) and Leu(242) in transmembrane domains II and V play a subtler role in controlling the metal specificity of hZnT10. Interestingly, the His → Asn reversion mutant in hZnT1 conferred manganese transport activity and loss of zinc transport activity. These results provide important information about manganese detoxification/efflux mechanisms in vertebrate cells as well as the molecular characterization of hZnT10 as a manganese transporter.
authors.affiliation: From the Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Yukina
authors.initials: Y
authors.lastname: Nishito
authors.affiliation: From the Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Natsuko
authors.initials: N
authors.lastname: Tsuji
authors.affiliation: the Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Fujishiro
authors.affiliation: From the Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Taka-Aki
authors.initials: TA
authors.lastname: Takeda
authors.affiliation: From the Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: From the Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan.
authors.forename: Fumie
authors.initials: F
authors.lastname: Teranishi
authors.affiliation: the Department of Food Science, Kyoto Women's University, Kyoto 605-8501, Japan.
authors.forename: Fumiko
authors.initials: F
authors.lastname: Okazaki
authors.affiliation: the Department of Food Science, Kyoto Women's University, Kyoto 605-8501, Japan.
authors.forename: Ayu
authors.initials: A
authors.lastname: Matsunaga
authors.affiliation: the Clinical and Molecular Genetics Unit, University College London Institute of Child Health, London WC1N 1EH, United Kingdom.
authors.forename: Karin
authors.initials: K
authors.lastname: Tuschl
authors.affiliation: the Department of Physiology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland 21205, and.
authors.forename: Rajini
authors.initials: R
authors.lastname: Rao
authors.affiliation: the First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kono
authors.affiliation: the First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Miyajima
authors.affiliation: the Department of Food Science, Kyoto Women's University, Kyoto 605-8501, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Narita
authors.affiliation: the Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan.
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Himeno
authors.affiliation: From the Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan, kambe1@kais.kyoto-u.ac.jp.
authors.forename: Taiho
authors.initials: T
authors.lastname: Kambe
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D027682:Cation Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D055785:Gene Knockdown Techniques; D008345:Manganese / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: D027682:Cation Transport Proteins; D008345:Manganese
keywords: ATP13A family protein; SPCA1; efflux; ferroportin; manganese; metal homeostasis; substrate specificity; transporter; zinc