Sequence Determinants of Amyloid Fibril Formation

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...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2004-01, Vol.101 (1), p.87-92
Main Authors: de la Paz, Manuela López, Serrano, Luis
Format: Article
Language:English
Subjects:
Aggregation
Amino Acid Motifs
Amino Acid Sequence
Amino acids
Amyloid - chemistry
Amyloid - genetics
Amyloid - metabolism
Amyloids
Animals
Biological Sciences
Disease
Experiments
Humans
In Vitro Techniques
Molecules
Mutagenesis, Insertional
Mutation
Oligopeptides - chemistry
Oligopeptides - genetics
Oligopeptides - metabolism
Polymerization
Protein Structure, Secondary
Proteins
Ratios
Solar fibrils
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 β-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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2634884100