Table 1.
Summary of the known post-translational modifications of α-synuclein, and of their effects on its binding to lipid membranes.
| Post-translational modifications | Position | Lipid membranes | Reported effects on lipid membranes | Reported functional impact | References |
|---|---|---|---|---|---|
| Acetylation | M1 | DOPE/DOPS/DOPC synaptic-like vesicles | Increases the affinity but does not affect the structure | Regulates the binding to synaptic vesicles | (108) |
| High-curvature synaptic-like vesicle | “ | “ | (109) | ||
| SUVs with lipid rafts (DOPC/SM/Chol) | “ | “ | |||
| Giant cell membrane-derived plasma vesicles | “ | “ | (110) | ||
| DOPE/DOPS/DOPC synaptic-like vesicles | “ | “ | (111) | ||
| Non-ionic detergent BOG | “ | “ | (112) | ||
| DOPE/DOPS/DOPC synaptic-like vesicles | “ | “ | |||
| Synaptosomal membranes | No difference | (113) | |||
| POPG LUVs | “ | ||||
| POPC/POPS/Chol LUVs synaptic-like vesicles | “ | ||||
| HeLa cell cellular membranes | “ | ||||
| Phosphorylation | S129 | Synaptosomes from mouse brains | Does not affect the wild-type, but affects A30P (increase) and A53T (decrease) membrane binding | (114) | |
| SN dopaminergic neurons internalised vesicles | Disruption of vesicles increased by fibrils with pS129 | Upregulation of the pathology | |||
| Y39 | SUV synaptic vesicle mimic | Disruption of the helix-2 binding region | May lead to interaction with other proteins and vesicles, resulting in aggregation | (115) | |
| S87 | POPG vesicles and SDS micelles | Decreases binding affinity | “ | (116) | |
| S129 | POPG vesicles and SDS micelles | No difference | |||
| S129 | POPG | Fibril-induced rupture of lipid membranes | Upregulation of pathology | (117) | |
| Ubiquitination | K63 | Endosomal membranes | Increases internalization and localisation | Regulation of degradation | (118) |
| K6 | POPG vesicles | No difference | (119) | ||
| SUMOylation | Unspecific | Extracellular vesicles | Enhances binding | May enhance spreading | (120) |
| Nitration | Y39 | POPG | Decreases binding affinity | May increase interactions with other proteins and lipid vesicles, leading to aggregation | (121) |
| Y125 | |||||
| Non-specific | POPC/POPA UVs | “ | “ | (122) | |
| Y39 | POPC/POPS 1:1 | “ | “ | (123) | |
| Truncation | 1-119 | DMPS SUVs | Aggregates an order magnitude faster with SUVs | Increased aggregation | (124) |
| 1-103 | DMPS SUVs | Aggregates form mature fibrils rather than kinetically trapped protofibrils | Possible competent seed for secondary nucleation in vivo | ||
| 1-121 | POPG vesicles erythrocytes |
Decreases the ability to disturb lipid membranes | Protective in pathogenesis | (125) | |
| Glycation | S87 | POPG | No effect on binding affinity | (126) | |
| S87 | POPS | “ | |||
| T72 | POPG | “ | (127) | ||
| T72 | POPS | “ | |||
| T75 | POPG | “ | (128) | ||
| T81 | POPG | “ | |||
| S87 | POPG | “ | |||
| T72 | POPG | “ | |||
| T72/75/81 | POPG | Slight decrease in affinity | Possible regulation of membrane binding |