Ctr2 regulates biogenesis of a cleaved form of mammalian Ctr1 metal transporter lacking the copper- And cisplatin-binding ecto-domain

Helena Öhrvik, Yasuhiro Nose, L. Kent Wood, Byung Eun Kim, Sophie Charlotte Gleber, Martina Ralle, Dennis J. Thiele

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Copper is an essential catalytic cofactor for enzymatic activities that drive a range of metabolic biochemistry including mitochondrial electron transport, iron mobilization, and peptide hormone maturation. Copper dysregulation is associated with fatal infantile disease, liver, and cardiac dysfunction, neuropathy, and anemia. Here we report that mammals regulate systemic copper acquisition and intracellular mobilization via cleavage of the copper-binding ecto-domain of the copper transporter 1 (Ctr1). Although full-length Ctr1 is critical to drive efficient copper import across the plasma membrane, cleavage of the ecto-domain is required for Ctr1 to mobilize endosomal copper stores. The biogenesis of the truncated form of Ctr1 requires the structurally related, previously enigmatic copper transporter 2 (Ctr2). Ctr2-/- mice are defective in accumulation of truncated Ctr1 and exhibit increased tissue copper levels, and X-ray fluorescence microscopy demonstrates that copper accumulates as intracellular foci. These studies identify a key regulatory mechanism for mammalian copper transport through Ctr2-dependent accumulation of a Ctr1 variant lacking the copper-and cisplatin-binding ecto-domain.

Original languageEnglish (US)
Pages (from-to)E4279-E4288
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number46
DOIs
StatePublished - Nov 12 2013

Keywords

  • Endosome
  • Lysosome
  • Platinum
  • Protein regulation
  • Uptake

ASJC Scopus subject areas

  • General

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