parkin

Parkin is a 465-amino-acid E3 ubiquitin ligase encoded by the PARK2 gene in humans. The PARK2 gene is on chromosome 6q25.2-q27. Parkin contains an N-terminal ubiquitin-like (Ubl) domain and a C-terminal arrangement of RING0, RING1, and RING2/IBR domains, which together support its ubiquitin‑ligase activity.

Parkin is central to mitochondrial quality control through mitophagy. When mitochondria are damaged, the serine/threonine kinase PINK1 accumulates on the outer mitochondrial membrane and phosphorylates Parkin and ubiquitin at Ser65, activating Parkin. Active Parkin ubiquitinates several outer membrane proteins, promoting their recognition by autophagy receptors and the selective degradation of damaged mitochondria.

Clinical significance. Mutations in PARK2 are among the most common genetic causes of early-onset Parkinson’s disease, usually inherited in an autosomal recessive manner. Affected individuals commonly develop symptoms before age 50, with rigidity, bradykinesia, and tremor, and may show slower progression compared with other PD forms. Heterozygous PARK2 variants have been reported in some PD cases, but their contribution to disease risk is less well defined.

Other roles. Beyond neurodegeneration, Parkin participates in broader cellular processes including proteostasis, mitochondrial dynamics, and responses to cellular stress. Ongoing research seeks to understand Parkin’s substrate repertoire and to develop therapies that enhance mitophagy or compensate for Parkin loss.