Beta-sheet folding of 11-kDa fibrillogenic polypeptide is completely aggregation driven |
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Authors: | Topilina Natalya I Ermolenkov Vladimir V Higashiya Seiichiro Welch John T Lednev Igor K |
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Affiliation: | Department of Chemistry, University at Albany, SUNY, 1400 Washington Avenue, Albany, NY 12222, USA. |
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Abstract: | A de novo polypeptide GH(6)[(GA)(3)GY(GA)(3)GE](8)GAH(6) (YE8) was designed and genetically engineered to form antiparallel beta-strands of GAGAGA repeats. Modulation of pH enables control of solubility, folding, and aggregation of YE8 by control of the overall polypeptide charge, a consequence of the protonation or deprotonation of the glutamic acid and histidine residues. YE8 exhibits all the major properties of a fibrillogenic protein providing an excellent model for detailed study of the fibrillation. At neutral pH, YE8 is soluble in disordered form, yet at pH 3.5 folds into a predominantly beta-sheet conformation that is fibrillogenic. Atomic force microscopy and transmission electron microscopy indicated the formation of fibrillar aggregates on well-defined, hydrophobic surfaces. The beta-sheet folding of YE8 exhibited a lag phase that could be eliminated by seeding or stirring. The strong dependence of lag time on polypeptide concentration established the limiting step in aggregation as initiation of beta-sheet folding. |
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Keywords: | Raman spectroscopy protein folding protein secondary structure amyloid fibril |
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