Thomas V. O'Halloran Metalloregulatory proteins

Research Interests

We are exploring the cell and molecular biology of transition elements. One of our approaches is to isolate novel receptors and characterize their function, structure, and chemical mechanism. In other strategies, we are interrogating the vesicular trafficking of these elements by developing vital fluorescent probes that are specific for metal ions such as Zn(II). Together, these types of experiments are delineating elemental aspects of microbial and mammalian biology.

Two new classes of metalloprotein have emerged from these studies. Metalloregulatory proteins such as MerR, Fur, Zur, PcoRS, and ZntR act as metal responsive genetic switches. Our goal in studies of these proteins is to understand the basis of metal ion recognition, establish the mechanisms by which metal binding alters gene expression and ultimately uses these insights to describe global aspects of metal metabolism.

Metallochaperones are diffusible metal ion receptors involved in intracellular metal trafficking. It has long been thought that metalloproteins are highly specific chelators that select available metal ions in the cytoplasm of the cell. Our recent studies indicate the opposite: the 'free' copper concentration is lower than one atom per cell; too low to allow a protein to acquire copper without assistance. Atxl, a prototypical metallochaperone, protects and guides Cu(I) to a specific target enzyme in the cytoplasm. In humans, Atxl delivers Cu(I) to proteins involved in fatal metal-based disorders such as Menkes' syndrome and Wilson disease. Characterization of CCS, copper chaperone for superoxide dismutase, is another challenge, but has payoffs in our understanding and treatment of severe neurodegenerative diseases such as ALS.

Selected Publications

Zinc availability during germline development impacts embryo viability in Caenorhabditis elegansMendoza AD, Woodruff TK, Wignall SM, and O'Halloran TV. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology. 2017 January;191:194-202.

The zinc spark is an inorganic signature of human egg activation. Duncan FE, Que EL, Zhang N, Feinberg EC, O'Halloran TV, and Woodruff TK. Scientific Reports. 2016 April 26;6:24737.

The fertilization-induced zinc spark is a novel biomarker of mouse embryo quality and early development. Zhang N, Duncan FE, Que EL, O'Halloran TV, and Woodruff TK. Scientific Reports. 2016 March 18;6:22772.

Allosteric transcriptional regulation via changes in the overall topology of the core promoterPhilips SJ, Canalizo-Hernandez M, Yildirim I, Schatz GC, Mondragón A, and O'Halloran TV. Science. 2015 August 21;349(6250):877-881.

The inorganic anatomy of the mammalian preimplantation embryo and the requirement of zinc during the first mitotic divisions. Kong BY, Duncan FE, Que EL, Xu Y, Vogt S, O'Halloran TV, and Woodruff TK. Developmental Dynamics. 2015 August;244(8):935-947.

View all publications by Thomas V. O'Halloran in the National Library of Medicine (PubMed). Current and former IBiS students in blue.