The aggregation of proteins in Alzheimer's, Parkinson's, prion diseases, Huntington's, and other amyloid-like diseases will be illuminated by methods of structural and computational biology. Background research by microcrystallography has shown that the fundamental structural unit of amyloid-like fibrils is a set of beta sheets, in which the amino acid sidechains of neighboring sheets intermesh, in what is termed a steric zipper. The steric zipper interface between the faces of the sheets is completely dry. The protein segments that form the sheets are as short as 4-8 residues in length, stacking either in parallel or antiparallel to grow a fibril, but the segments can be longer and some proteins contain several such segments. To learn the structures of amyloid fibrils from disease-associated proteins, the same methods of microcrystallography will be applied to microcrystals grown from short segments of the A? and Tau proteins of Alzheimer's disease, from the PrP protein of the prion diseases, from ?-synuclein of Parkinson's disease, and from proteins involved in ALS and diabetes type 2. To learn what happens during fibril formation to the rest of the protein, structural studies will also be conducted on larger segments and entire fibril-forming proteins, using novel methods of crystal screening and microcrystallography. Preliminary work shows that computational energetics can identify which segments from proteins are those that are fibril-forming and can be grown into microcrystals, suitable for structural determination. This procedure is based on the 3D Profile method for finding sequences that fit a given fold (in this case the steric zipper), using energy functions. The procedure will be extended and applied to amyloids. Once a segment has been discovered which forms fibrils, and its structure has been determined by crystallography as belonging to the steric-zipper type of architecture, the connection between the segment and fibrils of the full protein can be assessed by whether the segment can seed the full protein into fibrils. Further proof of the connection of the segment and fibrils of the full protein can be obtained by mutating residues in the protein that correspond to residues of the segment, and looking for diminished fibrillization. These structures, derived by novel methods of microcrystallography, are the first high-resolution (up to 0.85 A resolution), fully refined atomic structures for the amyloid state. They show that there are at least 4 basic patterns for the steric zipper spines of amyloid fibrils, and perhaps up to 7 such patterns. These structures offer a solid foundation on which to devise diagnostics and therapeutics for these devastating neurodegenerative diseases.
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