A short motif in the N-terminal region of α-synuclein is critical for both aggregation and function
| Autor: | David J. Brockwell, Sarah C. Good, Patricija van Oosten-Hawle, G. Nasir Khan, Jemma Makepeace, Ciaran P. A. Doherty, Roberto Maya-Martinez, Sheena E. Radford, Sabine M. Ulamec |
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| Rok vydání: | 2020 |
| Předmět: |
Vesicle fusion
Proteolipids Genetic Vectors Gene Expression Sequence alignment Phosphatidylserines Protein aggregation Article Protein Aggregates 03 medical and health sciences 0302 clinical medicine Bacterial Proteins Genes Reporter Structural Biology Gene expression Escherichia coli Animals Humans Amino Acid Sequence Cloning Molecular Caenorhabditis elegans Molecular Biology Gene Peptide sequence 030304 developmental biology Neurons 0303 health sciences biology Chemistry Parkinson Disease Hydrogen-Ion Concentration biology.organism_classification Recombinant Proteins Cell biology Disease Models Animal Luminescent Proteins alpha-Synuclein Protein Multimerization Sequence motif Sequence Alignment 030217 neurology & neurosurgery |
| Zdroj: | Nature structural & molecular biology |
| ISSN: | 1545-9985 1545-9993 |
| DOI: | 10.1038/s41594-020-0384-x |
| Popis: | Aggregation of human α-synuclein (αSyn) is linked to Parkinson’s disease (PD) pathology. The central region of the αSyn sequence contains the non-amyloid β-component (NAC) crucial for aggregation. However, how NAC flanking regions modulate αSyn aggregation remains unclear. Using bioinformatics, mutation, and NMR we identify a 7-residue sequence, named P1 (residues 36-42), that controls αSyn aggregation. Deletion or substitution of this ‘master-controller’ prevents aggregation at pH 7.5 in vitro. At lower pH, P1 synergises with a sequence containing the PreNAC region (P2, residues 45-57) to prevent aggregation. Deleting P1 (ΔP1) or both P1 and P2 (ΔΔ) also prevents age-dependent αSyn aggregation and toxicity in C. elegans models and prevents αSyn-mediated vesicle fusion by altering the conformational properties of the protein when lipid-bound. The results highlight the importance of a master-controller sequence motif that controls both αSyn aggregation and function- a region that could be targeted to prevent aggregation in disease. |
| Databáze: | OpenAIRE |
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