E46K Mutation of α-Synuclein Preorganizes the Intramolecular Interactions Crucial for Aggregation
Defa Huang, Cong Guo
Abstract
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 43 KTKK 46 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.