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.

由 PARK2 基因编码的 parkin 突变与一种罕见的帕金森病有关，称为常染色体隐性遗传性青少年帕金森病 (ARJP)。Parkin 是 E3 泛素连接酶 RBR 家族的成员。Parkin 包含一个 RING1-In-Between-Ring (IBR)-RING2 基序。IBR 结构域位于 parkin 蛋白的 C 末端。IBR 域中存在两个锌结合位点，显示出依赖于锌离子的折叠并保持 RING 域的方向和几何形状。因此，锌结合区域的突变可能是导致 parkin 蛋白折叠不当的原因，最终会影响蛋白质的结构和功能。Parkin 蛋白的异常会增加脑细胞中错误折叠蛋白的聚集。结果，发生细胞毒性。IBR 结构域还与属于 E2 蛋白家族的 UbcH7 和 UbcH8 蛋白相互作用，并促进 Synphilin-1、Sept5 和 SIM2 蛋白泛素化。据报道，parkin 蛋白的错义突变是导致常染色体隐性幼年帕金森病的原因。在这项工作中，我们首先从文献和序列数据库中收集了 IBR 域中的错义突变。然后，使用各种计算工具，我们预测了它们的致病性和导致各种蛋白质特性可能发生变化的参与。分析了氨基酸的进化保守性、溶剂可及表面积、理化性质和蛋白质结构的变化。我们首次分析了parkin 中这些突变的影响，以破译帕金森病的合理分子机制。