title: Combinatorial approaches to probe the sequence determinants of protein aggregation and amyloidogenicity.
abstract: Elucidation of the molecular determinants that drive proteins to aggregate is important both to advance our fundamental understanding of protein folding and misfolding, and as a step towards successful intervention in human disease. Combinatorial strategies enable unbiased and model-free approaches to probe sequence/structure relationships. Through the use of combinatorial methods, it is possible (i) to probe the sequence determinants of natural amyloid proteins by screening libraries of amino acid substitutions (mutations) to identify those that prevent amyloid formation; and (ii) to test new hypotheses about the mechanism of formation of amyloid fibrils by using these hypotheses to guide the design of combinatorial libraries of de novo amyloid-like proteins. Here, we review how these two approaches have been used to study the molecular determinants of protein aggregation and amyloidogenicity.
authors.affiliation: Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Wurth
authors.forename: Woojin
authors.initials: W
authors.lastname: Kim
authors.forename: Michael H
authors.initials: MH
authors.lastname: Hecht
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019151:Peptide Library; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D000682:Amyloid; D019151:Peptide Library