Protein degradation is a major process in the cell, allowing control and adjustment of the levels of proteins. The enzyme responsible for the vast majority of cellular protein degradation is the 26S proteasome¹. Protein degradation is a highly regulated process that dependents on specific poly-ubiquitination of the substrate. The ubiquitination pathway is catalyzed by E1, E2 and E3 enzymes that activate, conjugate, and ligate, respectively, the ubiquitin protein to the substrate protein².

Parkin is a cytosolic E3 ubiquitin ligase that plays an important role in neuroprotection. Structurally, the Parkin protein is comprised of a ubiquitin-like (Ubl) domain at its N-terminus and a really interesting new gene (RING)1–in-between-ring (IBR) –RING2 domain and a zinc-chelating (RING0) domain at its C-terminus. E2 ubiquitin-conjugated enzymes are recruited to the RING1 domain where they transfer ubiquitin to the RING2 domain at the Parkin catalytic site. The ubiquitin is then transferred to the substrate protein, where it serves as a tag for recognition by the proteasome³.

Parkin activity prevent the accumulation and aggregation of damaged proteins and therefore it protects against unfolded protein stress. In addition, it is known to promote the elimination of aberrant mitochondria via mitophagy⁴. Mutations in Parkin have been associated with Parkinson’s disease (PD), Alzheimer’s disease and Huntington’s disease⁵.