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Table 1 Examples of parkin point mutations detected in Parkinson’s disease patients and their impacts on the structure and activity of the Parkin protein

From: Multitasking guardian of mitochondrial quality: Parkin function and Parkinson’s disease

Mutation Assignment based on clinical evidence using Sherloc Biochemical and functional consequences compared to wild-type Parkin
R42P Pathogenic Similar solubility [131] vs lower solubility [132, 134]
Increased solvent accessibility [139]
Formation of intracellular aggregates [131] vs similar diffuse distribution [134]
Retained autoubiquitination activity [131, 134]
Reduced stability [137, 138, 140]
Drastic changes in structure [139] that disrupt the autoinhibition state [16]
Translocating to mitochondria [23, 135, 137] vs no translocation to depolarized mitochondria [136]
Reduced mitophagy [136, 138] vs normal mitophagy [135]
Reduced phosphorylation by PINK1 [25]
A82E Benign Similar solubility [132, 134]
Similar diffuse distribution [107, 132, 134]
Retained autoubiquitination activity [134]
K161N Uncertain significance Similar solubility [131, 134] vs lower solubility [132]
Similar diffuse distribution [131]
Abolished [131] vs reduced [18] vs retained autoubiquitination activity [134]
Reduced ubiquitin chain synthesis [34]
Loss of charge in the putative phospho-binding site [137]
Translocation [135, 137] vs reduced translocation to depolarized mitochondria [23, 34, 86]
Reduced mitophagy [135]
K211N Pathogenic Similar solubility [132, 134]
Similar diffuse distribution [132]
Loss of charge in the putative phospho-binding site [137]
Retained autoubiquitination activity [134]
Reduced ubiquitin chain synthesis [34]
Reduced translocation to depolarized mitochondria [23, 34, 81, 86, 135, 137]
Reduced mitophagy [138]
C212Y Pathogenic Lower solubility [132]
Formation of intracellular aggregates [135, 138]
Suggested decreased protein stability [138]
Reduced translocation to depolarized mitochondria [81]
Reduced mitophagy [138]
T240R Likely
pathogenic
Similar solubility [131, 132]
Similar diffuse distribution [131, 132]
Abolished autoubiquitination activity [18, 131]
Significantly affected RING1-UBL binding [137] that affects E2 binding [2]
Reduced translocation to depolarized mitochondria [23, 34, 135,136,137]
Induce formation of mitochondrial aggregates [136]
Reduced mitophagy [136, 138]
R256C Uncertain significance Formation of intracellular aggregates [107, 131] vs similar diffuse distribution [134]
Lower solubility [131, 132] vs similar solubility [134]
Retained autoubiquitination activity [131, 134]
Minor structural variation [137]
Translocate to depolarized mitochondria and promote mitophagy [135]
R275W Likely
pathogenic
Lower solubility [131, 132, 134]
Formation of intracellular aggregates [107, 131, 132, 134, 138]
Retained autoubiquitination activity [131, 134]
Fail to promote ubiquitin chain synthesis [34]
Disrupt charge distribution and local rearrangements in the RING1-IBR interface [137]
Suggested decreased protein stability [138]
Translocate to depolarized mitochondria [135,136,137]
Reduced mitophagy [135, 136, 138]
G328E Uncertain significance Similar solubility [131, 134] vs lower solubility [132]
Similar distribution [107, 131, 134]
Retained activity [131, 134] vs reduced autoubiquitination activity [18]
Loss of flexibility of the loop region and disturbances of backbone arrangement [137]
Translocate to depolarized mitochondria and promote mitophagy [86, 135]
R334C Benign Lower solubility [132]
No effect on domain stability [137]
Translocate to depolarized mitochondria and promote mitophagy [135] vs increase mitophagy [138]
T415N Pathogenic Similar solubility [131, 132]
Similar distribution [131, 132]
Abolished autoubiquitination activity [44, 86, 131]
Disturbance of backbone arrangement [137]
Reduced translocation to depolarized mitochondria [23, 136, 137]
Induce formation of mitochondrial aggregates [136]
Reduced mitophagy [136, 138]
C418R Uncertain significance Lower solubility [134]
Formation of intracellular aggregates [134, 135]
Increased solvent accessibility [133]
Abolished autoubiquitination activity [134]
G430D Likely
pathogenic
Lower solubility [131] vs similar solubility [132]
Similar diffuse distribution [131, 132]
Retained autoubiquitination activity [131] vs abolished autoubiquitination activity [44, 86]
Reduced ubiquitin chain synthesis [34]
Reduced translocation to depolarized mitochondria [23, 34, 135, 137]
Reduced mitophagy [138]
C431F Pathogenic Lower solubility [131, 132]
Similar diffuse distribution [107] vs forming intracellular aggregates [131]
Retained autoubiquitination activity [131] vs abolished autoubiquitination activity [44]
High local destabilization and loss of the catalytic centre [137]
Reduced translocation to depolarized mitochondria [137]
Reduced mitophagy [138]
C441R Pathogenic Lower solubility [132, 134]
Formation of intracellular aggregates [132, 134, 135, 138]
Increased solvent accessibility [133]
Abolished autoubiquitination activity [44, 134]
Do not translocate to depolarized mitochondria [81]
Suggested decreased protein stability [138]