A pH-dependent switch promotes ?-synuclein fibril formation via glutamate residues.

ABSTRACT: ?-Synuclein (?S) is the primary protein associated with Parkinson's disease, and it undergoes aggregation from its intrinsically disordered monomeric form to a cross-? fibrillar form. The closely related homolog ?-synuclein (?S) is essentially fibril-resistant under cytoplasmic physiological conditions. Toxic gain-of-function by ?S has been linked to dysfunction, but the aggregation behavior of ?S under altered pH is not well-understood. In this work, we compare fibril formation of ?S and ?S at pH 7.3 and mildly acidic pH 5.8, and we demonstrate that pH serves as an on/off switch for ?S fibrillation. Using ?S/?S domain-swapped chimera constructs and single residue substitutions in ?S, we localized the switch to acidic residues in the N-terminal and non-amyloid component domains of ?S. Computational models of ?S fibril structures indicate that key glutamate residues (Glu-31 and Glu-61) in these domains may be sites of pH-sensitive interactions, and variants E31A and E61A show dramatically altered pH sensitivity for fibril formation supporting the importance of these charged side chains in fibril formation of ?S. Our results demonstrate that relatively small changes in pH, which occur frequently in the cytoplasm and in secretory pathways, may induce the formation of ?S fibrils and suggest a complex role for ?S in synuclein cellular homeostasis and Parkinson's disease.

SUBMITTER: Moriarty GM 

PROVIDER: S-EPMC5625065 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature