Control over the intracellular distribution of essential metal ions is necessary for living organisms. How are metal ions delivered to their appropriate targets? In the case of copper, it was recently established that the concentration of free copper ions is less than one atom per cell in yeast. The cytoxicity of free metal ions such as copper is a compelling reason for such an extraordinary level of control over their concentration. Yet, this result appears to create a new dilemma in describing the distribution of metal ions in the cell. Given the extremely slow rates of dissociation for metal ions from their metal binding proteins, can metal ion allocation be under thermodynamic control? The recent discovery of metallochaperones which facilitate the delivery of their metal ion cargo to specific partner proteins raises the possibility that metal on delivery is kinetically controlled: metallochaperones serve as catalysts in metal transfer events with their intended targets. The proposed research aims to test the hypothesis of kinetically controlled cellular distribution of metal ions. Yeast have proven to be a good model ion trafficking in which a number of metallochaperones have been identified and characterized. The Atx1 Cu(l) chaperon and its target, the Ccc2 P-type ATPase, are structurally and functionally well characterized and provide an excellent system for probing aspects of the mechanism and kinetics of Cu(l) transfer. This system bears significant homology and functional similarity with the Menkes and Wilson disease proteins and their Cu(l) chaperone.
| Xue, Yi; Davis, Anna V; Balakrishnan, Gurusamy et al. (2008) Cu(I) recognition via cation-pi and methionine interactions in CusF. Nat Chem Biol 4:107-9 |
| Davis, Anna V; O'Halloran, Thomas V (2008) A place for thioether chemistry in cellular copper ion recognition and trafficking. Nat Chem Biol 4:148-51 |
