The Importance of Being Capped: Terminal Capping of an Amyloidogenic Peptide Affects Fibrillation Propensity and Fibril Morphology

Maria Andreasen, Katrine Kirkeby Skeby, Shuai Zhang, Erik Holm Nielsen, Lasse Hyldgaard Klausen, Heidi Frahm, Gunna Christiansen, Troels Skrydstrup, Mingdong Dong, Birgit Schiøtt, Daniel Otzen

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Abstract

The formation of aggregated fibrillar β-sheet structures has been proposed to be a generic feature of proteins. Aggregation propensity is highly sequence dependent, and often only part of the protein is incorporated into the fibril core. Therefore, shorter peptide fragments corresponding to the fibril core are attractive fibrillation models. The use of peptide models introduces new termini into the fibrils, yet little attention has been paid to the role these termini may play in fibrillation. Here, we report that terminal modifications of a 10-residue peptide fragment of human islet amyloid polypeptide strongly affect fibrillation kinetics and the resulting fibril morphology. Capping of the N-terminus abolishes fibrillation, while C-terminal capping results in fibrils with a twisted morphology. Peptides with either both termini free or both termini capped form flat fibrils. Molecular dynamics simulations reveal that the N-terminal acetyl cap folds up and interacts with the peptide's hydrophobic side chains, while the uncapped N-terminus in the C-terminally capped version results in twisting of the fibrils due to charge repulsion from the free N-termini. Our results highlight the role of terminal interactions in fibrillation of small peptides and provide molecular insight into the consequences of C-terminal modifications frequently found in peptide hormones in vivo.

OriginalsprogEngelsk
TidsskriftBiochemistry
Vol/bind53
Nummer44
Sider (fra-til)6968-6980
Antal sider13
ISSN0006-2960
DOI
StatusUdgivet - 21 okt. 2014

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