title: Sequence determinants of amyloid fibril formation.
abstract: The establishment of rules that link sequence and amyloid feature is critical for our understanding of misfolding diseases. To this end, we have performed a saturation mutagenesis analysis on the de novo-designed amyloid peptide STVIIE (1). The positional scanning mutagenesis has revealed that there is a position dependence on mutation of amyloid fibril formation and that both very tolerant and restrictive positions to mutation can be found within an amyloid sequence. In this system, mutations that accelerate beta-sheet polymerization do not always lead to an increase of amyloid products. On the contrary, abundant fibrils are typically found for mutants that polymerize slowly. From these experiments, we have extracted a sequence pattern to identify amyloidogenic stretches in proteins. The pattern has been validated experimentally. In silico sequence scanning of amyloid proteins also supports the pattern. Analysis of protein databases has shown that highly amyloidogenic sequences matching the pattern are less frequent in proteins than innocuous amino acid combinations and that, if present, they are surrounded by amino acids that disrupt their aggregating capability (amyloid breakers). This study provides the potential for a proteome-wide scanning to detect fibril-forming regions in proteins, from which molecules can be designed to prevent and/or disrupt this process.
authors.affiliation: European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany. delapaz@embl.de
authors.forename: Manuela
authors.initials: M
authors.lastname: López de la Paz
authors.forename: Luis
authors.initials: L
authors.lastname: Serrano
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D006801:Humans; D066298:In Vitro Techniques; D016254:Mutagenesis, Insertional; D009842:Oligopeptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary
chemical_list: D000682:Amyloid; D009842:Oligopeptides