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

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, 135–137] 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 [135–137] 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]