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

Aggregation of & alpha;-synuclein is central to the pathogenesisof Parkinson's disease. The most toxic familial mutation E46Kaccelerates the aggregation process by an unknown mechanism. Herein,we provide a clue by investigating the influence of E46K on monomeric & alpha;-synuclein and its relation to aggregation with molecular dynamicssimulations. The E46K mutation suppresses & beta;-sheet structuresin the N-terminus while promoting those at the key fibrillizationregion named NACore. Even though WT and E46K monomers share conservedintramolecular interactions with fibrils, E46K abolishes intramolecularcontacts within the N-terminus which are present in the WT monomerbut absent in fibrils. Network analysis identifies residues 36-53as the interaction core of the WT monomer. Upon mutation, residues36-46 are expelled to water due to aggravated electrostaticrepulsion in the (KTKK46)-K-43 segment. Instead,NACore (residues 68-78) becomes the interaction hub and connectspreceding residues 47-56 and the C-terminus. Consequently,residues 47-95 which belong to the fibril core form more compact & beta;-sheets. Overall, the interaction network of E46K is more likefibrils than WT, stabilizing the fibril-like conformations. Our workprovides mechanistic insights into the faster aggregation of the E46Kmutant. It implies a close link between monomeric conformations andfibrils, which would spur the development of therapeutic strategies.