Amanda Bird

Focus

Sensing of metal elements by eukaryotes; regulatory roles of novel RNAs and small proteins

Research interests

 

The primary focus of our lab is to understand how eukaryotic cells regulate intracellular zinc levels.  In humans, proteins that bind zinc may represent up to 9% of the human proteome.  Although zinc is essential for life, in excess, it is toxic to cell growth.  As a consequence, all cells need mechanisms to maintain zinc at an optimal level.  Our major goals are to identify how cells sense changes in intracellular zinc levels and characterize mechanisms used to conserve or increase intracellular zinc levels during conditions of zinc deficiency.

 

The only known eukaryotic transcription factor that ‘senses’ zinc deficiency is Zap1 from the yeast Saccharomyces cerevisiae.   Zap1 is active when cells are limited for zinc.  Under these conditions Zap1 regulates the expression of genes required for zinc uptake and compartmentalization.  Zap1 also conserves cellular zinc by down-regulating the expression of genes encoding abundant zinc-metalloproteins (e.g. ADH1)

 

 

 

 

 

 

One of the mechanisms that Zap1 uses to ‘sense’ zinc deficiency is a regulatory zinc finger pair motif.  A zinc finger pair is a zinc-binding motif that contains two zinc finger domains held together by a hydrophobic interface.  In Zap1, the regulatory zinc finger pair has two additional features.  A transactivation domain overlaps with the pair and the zinc bound to the pair is labile in nature. We hypothesis that the occupancy of these zinc fingers with zinc is lowered during zinc deficiency.  Under these conditions, the pair is not stably folded which exposes the transactivation domain.  One of the goals of the lab is to identify proteins that sense zinc in humans and characterize how they sense zinc.

 

Our second interest is to characterize mechanisms that cells use to survive zinc deficiency.  We have taken a transcriptomics based approach to identify novel transcripts that are induced during metal starvation in the yeast Schizosaccharomyces pombe.  We are currently characterizing the functions and regulatory roles of a number of novel proteins/RNAs that are induced during metal limitation. 

 

A large percent of the population are mildly zinc deficient.  Low levels of dietary zinc are an important factor that leading to an increased risk of esophageal and oral cancers while low serum zinc levels have been associated with an increased risk for coronary heart disease. Our work characterizing the basic zinc homeostatic machinery of a eukaryotic cell is crucial to understanding the roles of zinc in human nutrition and disease.

 

Dr. Bird has a joint appointment in the Department of Human Nutrition, College of Human Ecology, OSU.

 

 

Publications

• Khalimonchuk O, Bird AJ and Winge DR (2007) Evidence for a pro-oxidant intermediate in the assembly of cytochrome oxidase. J Biol Chem 282:17442-9
• Bird AJ (2007) Metallosensors, the ups and downs of gene regulation. Adv Microb Physiol 53:232-57