Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 103, Issue 47, Pages 17753-17758Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0606690103
Keywords
beta-sheet; beta-strand interaction; amyloid fibril; nanomaterial; protein engineering
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Funding
- NCRR NIH HHS [RR07707, P41 RR007707] Funding Source: Medline
- NIGMS NIH HHS [U54-GM074946, R01-GM57215, R01 GM057215, U54 GM074946] Funding Source: Medline
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Although the beta-rich self-assemblies are a major structural class for polypeptides and the focus of intense research, little is known about their atomic structures and dynamics due to their insoluble and noncrystalline nature. We developed a protein engineering strategy that captures a self-assembly segment in a water-soluble molecule. A predefined number of self-assembling peptide units are linked, and the beta-sheet ends are capped to prevent aggregation, which yields a mono-dispersed soluble protein. We tested this strategy by using Borrelia outer surface protein (OspA) whose single-layer beta-sheet located between two globular domains consists of two beta-hairpin units and thus can be considered as a prototype of self-assembly. We constructed self-assembly mimics of different sizes and determined their atomic structures using x-ray crystallography and NMR spectroscopy. Highly regular beta-sheet geometries were maintained in these structures, and peptide units had a nearly identical conformation, supporting the concept that a peptide in the regular beta-geometry is primed for self-assembly. However, we found small but significant differences in the relative orientation between adjacent peptide units in terms of beta-sheet twist and bend, suggesting their inherent flexibility. Modeling shows how this conformational diversity, when propagated over a large number of peptide units, can lead to a substantial degree of nanoscale polymorphism of self-assemblies.
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