CERM is currently working on a structural genomics project involving some classes of metalloproteins involved in the homeostasis of metals. Each organism possesses mecha-nisms of homeostatic regulation that allow the uptake of the quantity of metal necessary for the cell while preventing ac-cumulation over toxic levels. A category of proteins, called metallochaperones, is responsible for the transportation of metals in cells and their distribution to target enzymes or to ATPases that allow them to pass through membranes. We have characterized the structure, dynamics and protein-protein interactions of some of these systems in eukaryotes and prokaryotes. The principal metals we studied are: Cu, Ni, Zu and Cd. Natural mutations in some of these proteins lead to disease. We study the biophysical and structural characteristics of some mutants to understand their relationship with disease. Among the mutants we have studied is the human copper protein zinc superoxide dismutase (SOD1). Mutations in the SOD1 gene have been associated with some familial forms of a neurodegenerative disease of the motor neurons called Amyotrophic Lateral Sclerosis (ALS). Metallochaperones have also been identified in the mito-chondrion, where they have a role in the formation of iron-sulphur clusters and in the assembly of copper enzymes such as cytochrome c oxidase and SOD. Some proteins in-volved in these mechanisms have been structurally charac-terized and their interactions have been studied at the mole-cular level. We have identified a redox protein dependent machinery involving a disulfide relay system that determines the folding of a class of mitochondrial proteins. This disulfide exchange reaction between the oxidase mia40, which is the first protein involved in the oxidative folding pathway, and its substrates Cox17 and Tim10, has been characterized at the molecular level.



Structures of human proteins involved in copper homeostasis solved by CERM researchers.