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  • A short motif in the N-terminal region of α-synuclein is critical for both aggregation and function.

A short motif in the N-terminal region of α-synuclein is critical for both aggregation and function.

Nature structural & molecular biology (2020-03-12)
Ciaran P A Doherty, Sabine M Ulamec, Roberto Maya-Martinez, Sarah C Good, Jemma Makepeace, G Nasir Khan, Patricija van Oosten-Hawle, Sheena E Radford, David J Brockwell
ABSTRACT

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.

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α-Synuclein A53T human, recombinant, expressed in E. coli, N-terminal histidine tagged, ≥90% (SDS-PAGE), lyophilized powder