Publication: Metallochaperones Regulate Intracellular Copper Levels

Copper (Cu) toxicity is a problem of medical, agricultural, and environmental significance. Cu toxicity severely inhibits growth of plant roots significantly affecting their morphology; Cu overload also accounts for some of the most common metal-metabolism abnormalities and neuropsychiatric problems including Wilson’s and Menkes diseases. There is a large body of literature on how Cu enters and exits the cell; the kinetic and structural details of Cu translocation between trafficking, sensing, metabolic, and pumping proteins; and phenotypes associated with defects in metalloregulatory and efflux functions. Although the role of metallochaperones in Cu-cytotoxicity has been poorly studied, it has been observed that in animals deletion of metallochaperones results in elevated intracellular Cu levels along with overexpression of the P1-type ATPase efflux pump, ultimately causing malformation with high mortality. These observations are mechanistically explained by a predictive model of the Cu circuit in Halobacterium salinarum, which serves as an excellent model system for Cu trafficking and regulation in organisms with multiple chaperones. Constructed through iterative modeling and experimentation, this model accurately recapitulates known dynamical properties of the Cu circuit and predicts that intracellular Cu-buffering emerges as a consequence of the interplay of paralogous metallochaperones that traffic and allocate Cu to distinct targets.