Molecular Origin of pH‐Dependent Fibril Formation of a Functional Amyloid

• DOI: 10.1002/cbic.201402074
• Publication Date: 2014-06-20T14:43:30Z
• Authors: Ryan P. McGlinchey; Zhiping Jiang; Jennifer C. Lee
• Keywords: Amyloid (mycology); Residue (chemistry); Fibrillogenesis

Abstract Fibrils derived from Pmel17 are functional amyloids upon which melanin is deposited. of the repeat domain (RPT) form under strict melanosomal pH (4.5–5.5) and completely dissolve at pH≥6. To determine Glu residue responsible for this reversibility, aggregation single, double, quadruple Ala Gln mutants were examined by intrinsic Trp fluorescence, circular dichroism spectroscopy, transmission electron microscopy. Charge neutralization E404, E422, E425, or E430, located in putative amyloid‐forming region, modulated kinetics. Remarkably, removal a single negative charge one 16 carboxylic acids, shifted dependence full unit. Mutation E430 had little to no effect. We suggest that protonation E422 essential initiating amyloid formation other residues play an allosteric role fibril stability.