Abstract
Mutations in parkin, which is encoded by the PARK2 gene, are associated with a rare form of Parkinson’s disease called autosomal recessive juvenile parkinsonism (ARJP). Parkin is a member of RBR family of E3 ubiquitin ligase. Parkin contains a RING1-In-Between-Ring (IBR)-RING2 motif. The IBR domain is located at the C-terminal end of the parkin protein. Two zinc-binding sites are present in the IBR domain which shows zinc ion–dependent folding and maintains the orientation and geometry of RING domains. So, mutation in a zinc-binding region can be responsible for improper folding of parkin protein, which eventually affects the protein structure and function. Abnormalities in parkin protein increase the aggregation of mis-folded proteins in the brain cell. As a consequence, cellular toxicity occurs. The IBR domain also interacts with UbcH7 and UbcH8 proteins belonging to E2 protein family and facilitates synphilin-1, Sept5, and SIM2 protein ubiquitination. It is reported that missense mutation in parkin protein are responsible for autosomal recessive juvenile Parkinson disease. In this work, we first collected the missense mutations in the IBR domain from literature and sequence databases. Then, using various computational tools, we predicted their pathogenicity and involvements in causing possible changes in various protein properties. Evolutionary conservation of amino acids, solvent accessible surface areas, the physico-chemical properties, and changes of protein structure were analyzed. We, for the first time, analyzed the effects of these mutations in parkin to decipher the plausible molecular mechanism of Parkinson’s disease.
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This study is supported by the DBT-Sponsored Bioinformatics Center of Kalyani University (Grant no. BT/BI/25/001/2006), UGC-SAP-DRS-II, DST-PURSE-II.
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Angshuman Bagchi conceptualized the work. Sima Biswas performed the entire work. Sima Biswas and Angshuman Bagchi wrote the manuscript. All the authors agreed to submit the manuscript.
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Biswas, S., Bagchi, A. Mutational Impact on “in-Between-Ring” (IBR) Domain of PARKIN on Protein Stability and Function. Appl Biochem Biotechnol 193, 1603–1616 (2021). https://doi.org/10.1007/s12010-021-03491-2
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DOI: https://doi.org/10.1007/s12010-021-03491-2