Gene duplication and neo-functionalization in the evolutionary and functional divergence of the metazoan Copper transporters Ctr1 and Ctr2

Brandon L. Logeman, L. Kent Wood, Jaekwon Lee, Dennis J. Thiele

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Copper is an essential element for proper organismal development and is involved in a range of processes, including oxidative phosphorylation, neuropeptide biogenesis, and connective tissue maturation. The copper transporter (Ctr) family of integral membrane proteins is ubiquitously found in eukaryotes and mediates the high-affinity transport of Cu+ across both the plasma membrane and endomembranes. Although mammalian Ctr1 functions as a Cu+ transporter for Cu acquisition and is essential for embryonic development, a homologous protein, Ctr2, has been proposed to function as a low-affinity Cu transporter, a lysosomal Cu exporter, or a regulator of Ctr1 activity, but its functional and evolutionary relationship to Ctr1 is unclear. Here we report a biochemical, genetic, and phylogenetic comparison of metazoan Ctr1 and Ctr2, suggesting that Ctr2 arose over 550 million years ago as a result of a gene duplication event followed by loss of Cu+ transport activity. Using a random mutagenesis and growth selection approach, we identified amino acid substitutions inhumanand mouse Ctr2 proteins that support copper-dependent growth in yeast and enhance copper accumulation in Ctr1-/- mouse embryonic fibroblasts. These mutations revert Ctr2 to a more ancestral Ctr1-like state while maintaining endogenous functions, such as stimulating Ctr1 cleavage. We suggest key structural aspects of metazoan Ctr1 and Ctr2 that discriminate between their biological roles, providing mechanistic insights into the evolutionary, biochemical, and functional relationships between these two related proteins.

Original languageEnglish (US)
Pages (from-to)11531-11546
Number of pages16
JournalJournal of Biological Chemistry
Volume292
Issue number27
DOIs
StatePublished - Jan 1 2017

Fingerprint

Gene Duplication
Copper
Genes
Mutagenesis
Proteins
Oxidative Phosphorylation
Amino Acid Substitution
Fibroblasts
Cell membranes
Growth
Neuropeptides
Eukaryota
Connective Tissue
Yeast
Embryonic Development
Molecular Biology
Membrane Proteins
Substitution reactions
Yeasts
Cell Membrane

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Gene duplication and neo-functionalization in the evolutionary and functional divergence of the metazoan Copper transporters Ctr1 and Ctr2. / Logeman, Brandon L.; Wood, L. Kent; Lee, Jaekwon; Thiele, Dennis J.

In: Journal of Biological Chemistry, Vol. 292, No. 27, 01.01.2017, p. 11531-11546.

Research output: Contribution to journalArticle

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