Abstract
The supersecondary structure of amyloids and prions, proteins of intense clinical and biological interest, are difficult to determine by standard experimental or computational means. In addition, significant conformational heterogeneity is known or suspected to exist in many amyloid fibrils. Previous work has demonstrated that probability-based prediction of discrete β-strand pairs can offer insight into these structures. Here, we devise a system of energetic rules that can be used to dynamically assemble these discrete β-strand pairs into complete amyloid β-structures. The STITCHER algorithm progressively ‘stitches’ strand-pairs into full β-sheets based on a novel free-energy model, incorporating experimentally observed amino-acid side-chain stacking contributions, entropic estimates, and steric restrictions for amyloidal parallel β-sheet construction. A dynamic program computes the top 50 structures and returns both the highest scoring structure and a consensus structure taken by polling this list for common discrete elements. Putative structural heterogeneity can be inferred from sequence regions that compose poorly. Predictions show agreement with experimental models of Alzheimer’s amyloid beta peptide and the Podospora anserina Het-s prion. Predictions of the HET-s homolog HET-S also reflect experimental observations of poor amyloid formation. We put forward predicted structures for the yeast prion Sup35, suggesting N-terminal structural stability enabled by tyrosine ladders, and C-terminal heterogeneity. Predictions for the Rnq1 prion and alpha-synuclein are also given, identifying a similar mix of homogenous and heterogeneous secondary structure elements. STITCHER provides novel insight into the energetic basis of amyloid structure, provides accurate structure predictions, and can help guide future experimental studies.Proteins 2012. © 2011 Wiley Periodicals, Inc.
Highlights
Amyloid is a highly-ordered cross- protein aggregate that can be achieved by a very broad set of proteins with widely divergent and unrelated amino acid sequences [1,2]
We show that the STITCHER method can be used to accurately reconstruct structure, as is given by the example of the well-studied Alzheimer’s amyloid beta peptide and the Podospora anserina Het-s prion
Amyloid-beta: STITCHER was tested on amyloid beta, an amyloid with two experimental NMR models [20, 47], allowing both superpleated sheet and helix structures
Summary
Amyloid is a highly-ordered cross- protein aggregate that can be achieved by a very broad set of proteins with widely divergent and unrelated amino acid sequences [1,2]. A great many, perhaps most, proteins have the potential to form amyloids. A set of self-templating fungal amyloids give rise to epigenetic heritable traits. These bi-stable “prion” proteins can persist as soluble or amyloid species with different functional activities. The self-templating property causes cell-wide persistence of one or the other stable state, a status passed from generation to generation via cytoplasmic transfer of amyloid templates from mother to daughter cells[10,11]. Evidence suggests that the formation of amyloids may more commonly be a protective mechanism, which, especially in the case of the neurodegenerative amyloidoses, acts as to sequester misfolded polypeptides that would otherwise dwell in more toxic, and more highly interactive, oligomeric species. There is, great interest in deciphering the structures that underlie amyloid states
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