E46K Mutation of α-Synuclein Preorganizes the Intramolecular Interactions Crucial for Aggregation.

Aggregation of α-synuclein is central to the pathogenesis of Parkinson's disease. The most toxic familial mutation E46K accelerates the aggregation process by an unknown mechanism. Herein, we provide a clue by investigating the influence of E46K on monomeric α-synuclein and its relation to aggregation with molecular dynamics simulations. The E46K mutation suppresses β-sheet structures in the N-terminus while promoting those at the key fibrillization region named NACore. Even though WT and E46K monomers share conserved intramolecular interactions with fibrils, E46K abolishes intramolecular contacts within the N-terminus which are present in the WT monomer but absent in fibrils. Network analysis identifies residues 36-53 as the interaction core of the WT monomer. Upon mutation, residues 36-46 are expelled to water due to aggravated electrostatic repulsion in the KTKK segment. Instead, NACore (residues 68-78) becomes the interaction hub and connects preceding residues 47-56 and the C-terminus. Consequently, residues 47-95 which belong to the fibril core form more compact β-sheets. Overall, the interaction network of E46K is more like fibrils than WT, stabilizing the fibril-like conformations. Our work provides mechanistic insights into the faster aggregation of the E46K mutant. It implies a close link between monomeric conformations and fibrils, which would spur the development of therapeutic strategies.