The Importance of Being Capped: Terminal Capping of an Amyloidogenic Peptide Affects Fibrillation Propensity and Fibril Morphology
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- 作者：Maria Andreasen ; Katrine Kirkeby Skeby ; Shuai Zhang ; Erik Holm Nielsen ; Lasse Hyldgaard Klausen ; Heidi Frahm ; Gunna Christiansen ; Troels Skrydstrup ; Mingdong Dong ; Birgit Schi酶tt ; Daniel Otzen
- 刊名：Biochemistry
- 出版年：2014
- 出版时间：November 11, 2014
- 年：2014
- 卷：53
- 期：44
- 页码：6968-6980
- 全文大小：721K
- ISSN：1520-4995
文摘
The formation of aggregated fibrillar 尾-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鈥檚 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.