Structural and Functional Impact of Parkinson Disease‐Associated Mutations in the E3 Ubiquitin Ligase Parkin

摘要: Mutations in the PARKIN/PARK2 gene that result loss-of-function of encoded, neuroprotective E3 ubiquitin ligase Parkin cause recessive, familial early-onset Parkinson disease. As an increasing number rare sequence variants with unclear pathogenicity are identified, structure-function analyses will be critical to determine their disease relevance. Depending on specific amino acids affected, several distinct pathomechanisms can loss function. These include disruption overall folding, decreased solubility, and protein aggregation. However pathogenic effects also from misregulation autoinhibition its enzymatic functions. In addition, interference binding coenzymes, substrates, adaptor proteins affect catalytic activity too. Herein, we have performed a comprehensive structural functional analysis 21 PARK2 missense mutations distributed across individual domains. Using this combined approach, were able pinpoint some mechanisms variants. Similar gaining complete understanding complex regulations functions Parkin. studies not only highlight important residues, but help develop novel therapeutics aimed at activating preserving active, form