Expressional control of a cadmium-transporting P1B-type ATPase by a metal sensing degradation signal

David J. Adle, Jaekwon Lee

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Cadmium is a highly toxic environmental contaminant implicated in various diseases. Our previous data demonstrated that Pca1, a P1B-type ATPase, plays a critical role in cadmium resistance in yeast S. cerevisiae by extruding intracellular cadmium. This illustrates the first cadmium-specific efflux pump in eukaryotes. In response to cadmium, yeast cells rapidly enhance expression of Pca1 by a post-transcriptional mechanism. To gain mechanistic insights into the cadmium-dependent control of Pca1 expression, we have characterized the pathway for Pca1 turnover and the mechanism of cadmium sensing that leads to up-regulation of Pca1. Pca1 is a short-lived protein (t 1/2 < 5 min) and is subject to ubiquitination when cells are growing in media lacking cadmium. Distinct from many plasma membrane transporters targeted to the vacuole for degradation via endocytosis, cells defective in this pathway did not stabilize Pca1. Rather, Pca1 turnover was dependent on the proteasome. These data suggest that, in the absence of cadmium, Pca1 is targeted for degradation before reaching the plasma membrane. Mapping of the N terminus of Pca1 identified a metal-responding degradation signal encompassing amino acids 250-350. Fusion of this domain to a stable protein demonstrated that it functions autonomously in a metal-responsive manner. Cadmium sensing by cysteine residues within this domain circumvents ubiquitination and degradation of Pca1. These data reveal a new mechanism for substrate-mediated control of P1B-type ATPase expression. Cells have likely evolved this mode of regulation for a rapid and specific cellular response to cadmium.

Original languageEnglish (US)
Pages (from-to)31460-31468
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number46
DOIs
StatePublished - Nov 14 2008

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Cadmium
Adenosine Triphosphatases
Metals
Degradation
Ubiquitination
Cell membranes
Yeast
Yeasts
Cell Membrane
Membrane Transport Proteins
Poisons
Proteasome Endopeptidase Complex
Endocytosis
Vacuoles
Eukaryota
Cysteine
Saccharomyces cerevisiae
Proteins
Up-Regulation
Fusion reactions

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Expressional control of a cadmium-transporting P1B-type ATPase by a metal sensing degradation signal. / Adle, David J.; Lee, Jaekwon.

In: Journal of Biological Chemistry, Vol. 283, No. 46, 14.11.2008, p. 31460-31468.

Research output: Contribution to journalArticle

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