Metalloregulatory proteins; molecular mechanisms of metal-responsive gene expression; protein-DNA interactions; oxygen activation by nonheme iron proteins; bioinorganic chemistry

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.

Chen H, MacDonald RC, Li S, Krett NL, Rosen ST, O'Halloran TV. Lipid encapsulation of arsenic trioxide attenuates cytotoxicity and allows for controlled anticancer drug release. J Am Chem Soc. 2006 Oct 18;128(41):13348-9. No abstract available.

Deng HX, Shi Y, Furukawa Y, Zhai H, Fu R, Liu E, Gorrie GH, Khan MS, Hung WY, Bigio EH, Lukas T, Dal Canto MC, O'Halloran TV, Siddique T. Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria. Proc Natl Acad Sci U S A. 2006 May 2;103(18):7142-7. Epub 2006 Apr 24.

Furukawa Y, Fu R, Deng HX, Siddique T, O'Halloran TV. Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice. Proc Natl Acad Sci U S A. 2006 May 2;103(18):7148-53. Epub 2006 Apr 24.

Furukawa Y, O'Halloran TV. Posttranslational modifications in Cu,Zn-superoxide dismutase and mutations associated with amyotrophic lateral sclerosis. Antioxid Redox Signal. 2006 May-Jun;8(5-6):847-67.

T.V. O'Halloran and V.C. Culotta (2000). "Metallochaperones, and intraceullular shuttle service for metal ions." J. biol. Chem. 275: 25057-25060.

C.E. Ouffen, F.W. Outlen, and T.V. O'Halloran (1999). "DNA Distortion Mechanism for transcriptional Activation by ZntR, and Zn(II) responsive MerR Homologue in E. coli." J. Biol. Chem. 274: 37517-37524.

A.C. Rosenzweig, D.L. Huffman, M.Y. Hou, A.K. Wernimont, and R.P. Pufahl (1999). "Crystal structure of the Atxl metallochaperone protein at 1.92A resolution ." Structure 7 : 605-617.

T.D. Rae, P.J. Schmidt, R.A. Pufahl, and V.C. Culotta (1999). "Undetectable free intracellular copper: the requirement of a copper chaperone for superoxide dismutase." Science: 805-808. (see also Perspective: "Free Copper Ions in the Cell" by S.J. Lippard, p. 748-749 in the same issue)

E.W. Althaus, C.E. Outten, K.E. Olson, and H. Cao (1999). "The ferric uptake regulation (Fur) repressor is a zinc metalloprotein." Biochemistry 38: 6559-6569.

D.A. Suhy, K.D. Simon, and D.I.H. Linzer (1999). "Metalloprotein is part of a zinc-scavenging mechanism for cell survival under conditions of extreme zinc deprivation. J. Bio. Chem. 274: 9183-9192.

P.J. Schmidt, T.D. Rae, R.A. Pufahl, J Strain, T. Hamma, and V.C. Culotta (1999). "Multiple protein domains contribute to the action of the copper chaperone for superoxide dismutase." J. Bio. Chem. 247: 23719-23725.

View all publications by publications by Thomas V. O'Halloran listed in the National Library of Medicine (PubMed).