Effects of N-terminal Acetylation on the Aggregation of Disease-related α-synuclein Variants. Issue 1 (15th January 2023)

• Record Type: Journal Article
• Authors: Bell, Rosie; Castellana-Cruz, Marta; Nene, Aishwarya; Thrush, Rebecca J.; Xu, Catherine K.; Kumita, Janet R.; Vendruscolo, Michele
• Is Part Of: Journal of molecular biology. Volume 435:Issue 1(2023)
• Publication Date: 2023-01-15
• Subjects: protein aggregation -- Parkinson's disease -- alpha-synuclein -- secondary nucleation -- oligomers; PD Parkinson's Disease -- WT Wild type -- acA30P N-terminally acetylated A30P α-synuclein -- acA53T N-terminally acetylated A53T α-synuclein -- acE46K N-terminally acetylated E56K α-synuclein -- acG51D N-terminally acetylated G51D α-synuclein -- acH50Q N-terminally acetylated H50Q α-synuclein -- acWT N-terminally acetylated WT α-synuclein -- SDS Sodium dodecyl sulphate -- DMPS 1, 2-dimyristoyl-sn-glycero-3-phospho-L-serine -- CD Circular dichroism -- SUV Small unilamellar vesicles -- TEM Transmission electron microscopy -- FTIR Fourier transform infrared -- PFF Pre-formed fibril -- DOPAL 3, 4-Dihydroxyphenylacetaldehyde; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2022.167825
• Languages: English
• ISSNs: 0022-2836

Abstract

Graphical abstract: Highlights: Familial mutations of alpha-synuclein have been linked with Parkinson's disease. N-terminal acetylation (NTA) of alpha-synuclein alters its aggregation behaviour. The effects of NTA aggregation process of familial mutants of alpha-synuclein is studied. A complex response of alpha-synuclein aggregation to chemical modification is identified. Abstract: Mutations in the SNCA gene, which encodes the protein α-synuclein, have been linked with early onset Parkinson's disease. The exact nature of this association, however, is still poorly understood. To investigate this problem, we started from the observation that α-synuclein is constitutively N-terminally acetylated, a post-translational modification that alters the charge and structure of α-synuclein molecules and affects their interaction with lipid membranes, as well as their aggregation process. We thus studied five N-terminal acetylated familial variants (A30P, E46K, H50Q, G51D and A53T) of α-synuclein through a wide range of biophysical assays to probe the microscopic steps in their aggregation process and the structures of the resulting aggregates. Our results reveal a great complexity in the combined effects of the disease-related mutations with N-terminal acetylation on the aggregation of α-synuclein, which underscores the great sensitivity to even relatively small perturbations of the behaviour of this protein.