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 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 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 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] |
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] |
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 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] |
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 | 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 | 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] |