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Molecular structure of amyloid and prion fibrils
Author(s) -
Tycko Robert
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.423.3
Subject(s) - fibril , amylin , amyloid (mycology) , amyloid fibril , peptide , chemistry , biophysics , peptide sequence , amyloid disease , solid state nuclear magnetic resonance , biochemistry , crystallography , amyloid β , biology , nuclear magnetic resonance , gene , medicine , disease , pathology , islet , inorganic chemistry , physics , insulin , endocrinology
At the end of the 20 th century, we knew that amyloid fibrils contain β‐sheets with a "cross‐β" orientation relative to the fibril's long axis, but nearly all other aspects of the molecular structures of amyloid fibrils were uncertain. By now, we have a much clearer picture of amyloid structures, largely due to solid state nuclear magnetic resonance (NMR) measurements that are capable of providing detailed constraints on secondary, tertiary, and quaternary structure within noncrystalline biopolymers. I will describe recent results from solid state NMR for fibrils formed by the Aβ peptide associated with Alzheimer's disease, the amylin peptide associated with type 2 diabetes, and yeast prion proteins (collaboration with Dr. Reed Wickner of the NIH). In particular, we have shown that the Aβ peptide can form a variety of fibrils with distinct molecular structures, and we have characterized two of the Aβ fibrils in detail, revealing the molecular basis for amyloid polymorphism. We have developed an experimentally‐based molecular model for amylin fibrils that is strikingly similar to molecular models for Aβ fibrils, despite significant differences in amino acid sequence and composition. We have demonstrated that in‐register parallel β‐sheets are nearly universal in amyloid fibrils, including those formed by yeast prion proteins. These results provide insight into the nature of the interactions that drive amyloid formation and that account for the nearly generic propensity of polypeptides to form amyloid fibrils. Finally, I will describe attempts to determine the molecular structures of Aβ fibrils that develop within the brain in Alzheimer's disease (collaboration with Dr. Stephen C. Meredith, University of Chicago).