Protein Structure Function
The ubiquitin-proteasome pathway (UPP) has emerged as a predominant cellular regulatory mechanism with roles in controlling cell-division, signal transduction, development and the immune response. It is also implicated in many neurodegenerative diseases, since cellular aggregates characterising neurodegeneration are heavily ubiquitinated. Mutations in p53 are linked to more than 50% of human cancers, making it an important protein in the understanding of cancer and cell biology.
p53 acts as a transcription factor and tumour suppressor. It was recently demonstrated that Parc (p53-associated Parkin-like cytoplasmic protein), a protein overexpressed in some neuroblastoma cell lines, anchors wild-type p53 in the cytoplasm, preventing its translocation to the nucleus and exerting its transcriptional and tumour suppressor roles. Structural characterisation of the interactions between Parc and p53 is necessary to understand how Parc retains p53 in the cytoplasm and how to disrupt this sequestration.
Parc encompasses two domains linked to the ubiquitin-conjugating cascade. One shares significant sequence homology with Cullin-7, an E3-ubiquitin-ligase, and the second resembles Parkin, another E3-ubiquitin-ligase, mutations in which are linked with an early-onset familial form of Parkinson's Disease. Structural information on Parkin would reveal how the mutations cause Parkinsonism and provide a scaffold for designing therapeutics to restore the function of Parkin.
A long-term research goal is to understand protein regulation in the brain, and implications in neurodegeneration and cell-cycle control. Specifically how, on a detailed molecular level, does Parc anchor p53 in the cytoplasm? How does Mdm2 regulate both p53 and synaptic proteins and what are the implications of these activities on protein regulation in the brain? How does the disruption of the normal function of Parkin lead to Parkinson's Disease? What are the mechanisms by which components of the ubiquitin-conjugation cascade effect protein regulation and cell-cycle control within the brain, and how do these control systems compare to those found in other organs?
The mechanisms of protein regulation systems within the brain are poorly understood. As well as the specialised requirement to maintain many of the cells in a post-mitotic state, the pathogenesis of many neurodegenerative diseases suggests that the destruction of abnormally folded and unfolded protein is a critical aspect of protein control in the brain. Dissection of the molecular mechanisms controlling protein turnover will not only enhance our understanding of these critical systems, but will also provide scaffolds for the design of therapeutics to target diseases, specifically Parkinson's Disease and neuroblastoma.
