2. Academic Validation
  3. Direct Comparison of Manganese Detoxification/Efflux Proteins and Molecular Characterization of ZnT10 Protein as a Manganese Transporter

Direct Comparison of Manganese Detoxification/Efflux Proteins and Molecular Characterization of ZnT10 Protein as a Manganese Transporter

  • J Biol Chem. 2016 Jul 8;291(28):14773-87. doi: 10.1074/jbc.M116.728014.
Yukina Nishito 1,  Natsuko Tsuji 1,  Hitomi Fujishiro 2,  Taka-Aki Takeda 1,  Tomohiro Yamazaki 1,  Fumie Teranishi 1,  Fumiko Okazaki 3,  Ayu Matsunaga 3,  Karin Tuschl 4,  Rajini Rao 5,  Satoshi Kono 6,  Hiroaki Miyajima 6,  Hiroshi Narita 3,  Seiichiro Himeno 2,  Taiho Kambe 7
Affiliations

Affiliations

  • 1 From the Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan.
  • 2 the Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, Japan.
  • 3 the Department of Food Science, Kyoto Women's University, Kyoto 605-8501, Japan.
  • 4 the Clinical and Molecular Genetics Unit, University College London Institute of Child Health, London WC1N 1EH, United Kingdom.
  • 5 the Department of Physiology, School of Medicine, The Johns Hopkins University, Baltimore, Maryland 21205, and.
  • 6 the First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.
  • 7 From the Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan, [email protected].
PMID: 27226609 DOI: 10.1074/jbc.M116.728014
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.

Keywords

ATP13A family protein; SPCA1; efflux; ferroportin; manganese; metal homeostasis; substrate specificity; transporter; zinc.

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