Transferrin receptor-like proteins control the degradation of a yeast metal transporter

EMBO J. 2006 Feb 22;25(4):662-72. doi: 10.1038/sj.emboj.7600984. Epub 2006 Feb 2.


Plasma membrane transporters are often downregulated by their substrates. The yeast manganese transporter Smf1 is subject to two levels of regulation: heavy metals induce its sequestration within the cell, and also its ubiquitination and degradation in the vacuole. Degradation requires Bsd2, a membrane protein with a PPxY motif that recruits the ubiquitin ligase Rsp5, and which has a role in the quality control of membrane proteins, that expose hydrophilic residues to the lipid bilayer. We show that degradation of Smf1 requires in addition one of a pair of related yeast proteins, Tre1 and Tre2, that also contain PPxY motifs. Tre1 can partially inhibit manganese uptake without Bsd2, but requires Bsd2 to induce Smf1 degradation. It has a relatively hydrophilic transmembrane domain and binds to Bsd2. We propose that the Tre proteins specifically link Smf1 to the Bsd2-dependent quality control system. Their luminal domains are related to the transferrin receptor, but these are dispensable for Smf1 regulation. Tre proteins and the transferrin receptors appear to have evolved independently from the same family of membrane-associated proteases.

MeSH terms

  • Amino Acid Motifs / physiology
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism*
  • Down-Regulation / drug effects
  • Down-Regulation / physiology
  • Endosomal Sorting Complexes Required for Transport
  • Evolution, Molecular
  • Gene Expression Regulation, Fungal / drug effects
  • Gene Expression Regulation, Fungal / physiology*
  • Ion Transport / physiology
  • Lipid Bilayers / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Metals, Heavy / pharmacology
  • Protein Structure, Tertiary / physiology
  • Saccharomyces cerevisiae / physiology*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Ubiquitin-Protein Ligase Complexes / genetics
  • Ubiquitin-Protein Ligase Complexes / metabolism*


  • BSD2 protein, S cerevisiae
  • Cation Transport Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Lipid Bilayers
  • Membrane Proteins
  • Metals, Heavy
  • SMF1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • TRE1 protein, S cerevisiae
  • Tre2 protein, S cerevisiae
  • Ubiquitin-Protein Ligase Complexes
  • RSP5 protein, S cerevisiae