A cytosolic domain of the yeast Zrt1 zinc transporter is required for its post-translational inactivation in response to zinc and cadmium.
Nutrient metals such as zinc are both essential to life and potentially toxic if overaccumulated by cells. Non-essential toxic metals like cadmium can enter cells through the uptake transporters responsible for nutrient metal acquisition. Therefore, in the face of ever changing extracellular metal levels, organisms tightly control their intracellular levels of nutrient metals and prevent accumulation of toxic metals. We show here that post-translational inactivation of the yeast Zrt1 zinc uptake transporter is important for zinc homeostasis. During the transition from zinc-limiting to zinc-replete growth conditions (i.e. zinc shock), the Zrt1 transporter is ubiquitinated, endocytosed, and subsequently degraded in the vacuole. To further understand this process at a molecular level, we mapped a region of Zrt1 required for ubiquitination and endocytosis in response to zinc to a domain located on the intracellular surface of the plasma membrane. This domain is a critical cis-acting component of the metal signaling pathway that controls Zrt1 protein trafficking. Using mutant alleles defective for metal-responsive inactivation, we also show that Zrt1 inactivation may be an important mechanism for preventing cadmium uptake and toxicity in zinc-limited cells.
Gitan
Raad S
RS
Department of Nutritional Sciences and Biochemistry, University of Missouri, Columbia, Missouri 65211, USA.
Shababi
Monir
M
Kramer
Michelle
M
Eide
David J
DJ
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002104:Cadmium / Q000378:metabolism / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D017124:Conserved Sequence; D003600:Cytosol / Q000378:metabolism; D006639:Histidine / Q000737:chemistry; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010449:Peptide Mapping; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology*
D027682:Cation Transport Proteins; D029701:Saccharomyces cerevisiae Proteins; C098750:ZRT1 protein, S cerevisiae; D002104:Cadmium; D006639:Histidine; D015032:Zinc