The study of the structure and dynamics of parkin activation
Abstract
Parkin is an RBR E3 ubiquitin ligase that has been implicated in both sporadic and familial Parkinson’s disease. Upon mitochondrial damage, parkin is activated step-wise to recruit and ligate ubiquitin to a substrate on the outer mitochondrial membrane. Disruption of this activation and ligation cascade is hypothesized to result in neuronal death related to Parkinson’s disease.
While structures of parkin for a number of these activation states exist, it is important to note they are not of full-length human parkin. These structures are often truncated and come from various non-human species to eliminate important, yet hard to quantify structural elements. Protein structure is important for deciphering function, but also only presents a partial story. To fully understand protein function, one must examine the changes that occur over time. Protein dynamics is the study of how proteins change over time.
To understand the intra- and inter-domain changes parkin undergoes during each step of activation, protein dynamics studies were undertaken in the slow to intermediate-fast time scales. The oligomeric state of parkin was also explored to further understand parkin ligation mechanisms. These approaches were used to create a more complete understanding of the functional- ity of parkin as an E3 ligase. Specifically, new models for each state of activation are proposed for the in vitro parkin pathway.
It was concluded that parkin acts monomerically throughout the various state changes. Further, parkin exhibits a number of conformational changes, not previously seen in the structures that help to elucidate its functionality. New structural models are proposed as a result of this work for a more complete model of parkin activation.