Biological inorganic chemistry of copper in the early ubiquitination pathways
The ubiquitination pathway is an essential post-translational modification (poly-ubiquitination) process for subsequent degradation of proteins by the proteasome.
Failures in this pathway may explain accumulation of proteins observed in many aged-related neurodegenerative diseases (such as Alzheimer’s, Parkinson’s and Huntington’s diseases). The pathway involves sequential actions by three classes of enzymes (E1, E2, E3) plus Mg-ATP.
Recent work by Opazo, Bush et al discovered that “physiological levels” of copper can regulate ubiquitination levels and protein degradation in tissue culture. Certain E2 enzymes were identified as the main targets of copper binding and regulation. This is a significant discovery, since copper homeostasis has long been recognized as a key contributing factor in cellular protein clearance. An understanding of the role of copper at the atomic level is essential to a molecular understanding of these key processes.
(1) Vilchez, D.; Saez, I.; Dillin, A., The role of protein clearance mechanisms in organismal ageing and age-related diseases, Nat. Commun. 2014, 5, 5659.
(2) Gadhave, K., et al, The ubiquitin proteasomal system: a potential target for the management of Alzheimer's disease, J. Cell. Mol. Med. 2016, 20, 1392-1407.
This project will express and isolate the enzyme targets identified by the in vivo study in order to undertake a systematic structure-function study to understand the molecular role of copper in ubiquitination.
Ms Ashwinie Ukuwela