Parkin structure and function

Abstract

Mutations in the parkin or PINK1 genes are the leading cause of the autosomal recessive form of Parkinson's disease. The gene products, the E3 ubiquitin ligase parkin and the serine/threonine kinase PINK1, are neuroprotective proteins, which act together in a mitochondrial quality control pathway. Here, we review the structure of parkin and mechanisms of its autoinhibition and function as a ubiquitin ligase. We present a model for the recruitment and activation of parkin as a key regulatory step in the clearance of depolarized or damaged mitochondria by autophagy (mitophagy). We conclude with a brief overview of other functions of parkin and considerations for drug discovery in the mitochondrial quality control pathway. Mutations in the parkin or PINK1 genes are leading causes of the autosomal recessive form of Parkinson's disease. The gene products are involved in a common pathway regulating clearance of depolarized mitochondria by mitophagy. In this review, we highlight key information derived from the parkin structure and provide a model for its recruitment and activation on mitochondria by phosphorylated ubiquitin.