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Amyloid fibrils are associated with many neurodegenerative diseases.1-3 Being formed from proteins unrelated functionally, amyloid fibrils share a common cross-β core structural motif and are considered to be an extraordinarily stable and energetically most favorable form of proteins.4,5 Recently we reported that temperature and salinity variations result in a substantial melting of the fibril core of mature apo-α-lactalbumin fibrils and in a spontaneous refolding to a different fibril polymorph.6 An important question to address is whether the described phenomenon is relevant to other protein fibrils.Our current findings indicate that a small pH change initiates the spontaneous transformation of insulin fibrils from one polymorph to another. Double-fiber-type fibrils with reverse VCD (vibrational circular dichroism) chirality form at pH 1.5, split into two separate proto-fibrils when the pH increases to 2.5 and intertwine to form left-handed twisted fibril polymorphs with normal VCD chirality. Using deep UV resonance Raman spectroscopy we demonstrate that the change of tyrosine local environments is taking place upon fibril spontaneous inter-conversion. At the same time, the fibril core has the same structure for both fibril polymorphs indicating that the pH-driven polymorphism of insulin fibrils is associated most probably with surface charge properties of proto-fibrils and the way they intertwine.7(1) Sipe, J. D.; Cohen, A. S. J Struct Biol 2000, 130, 88-98.(2) Makarava, N.; Baskakov, I. V. J Biol Chem 2008, 283, 15988-96.(3) Goldsbury, C. S.; Wirtz, S.; Muller, S. A.; Sunderji, S.; Wicki, P.; Aebi, U.; Frey, P. J Struct Biol 2000, 130, 217-31.(4) Gazit, E. Febs J 2005, 272, 5971-8.(5) Hartl, F. U.; Hayer-Hartl, M. Nat Struct Mol Biol 2009, 16, 574-81.(6) Kurouski, D.; Lauro, W.; Lednev, I. K. Chem Commun, 46, 4249-51.(7) Kurouski, D.; Lombardi, R. A.; Dukor, R. K.; Lednev, I. K.; Nafie, L. A. Chem Commun. |
