Antiparallel β-sheet architecture in Iowa-mutant β-amyloid fibrils
Open Access
- 8 March 2012
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (12), 4443-4448
- https://doi.org/10.1073/pnas.1111305109
Abstract
Wild-type, full-length (40- and 42-residue) amyloid β-peptide (Aβ) fibrils have been shown by a variety of magnetic resonance techniques to contain cross-β structures in which the β-sheets have an in-register parallel supramolecular organization. In contrast, recent studies of fibrils formed in vitro by the Asp23-to-Asn mutant of 40-residue Aβ (D23N-Aβ1–40), which is associated with early onset neurodegeneration, indicate that D23N-Aβ1–40 fibrils can contain either parallel or antiparallel β-sheets. We report a protocol for producing structurally pure antiparallel D23N-Aβ1–40 fibril samples and a series of solid state nuclear magnetic resonance and electron microscopy measurements that lead to a specific model for the antiparallel D23N-Aβ1–40 fibril structure. This model reveals how both parallel and antiparallel cross-β structures can be constructed from similar peptide monomer conformations and stabilized by similar sets of interactions, primarily hydrophobic in nature. We find that antiparallel D23N-Aβ1–40 fibrils are thermodynamically metastable with respect to conversion to parallel structures, propagate less efficiently than parallel fibrils in seeded fibril growth, and therefore must nucleate more efficiently than parallel fibrils in order to be observable. Experiments in neuronal cell cultures indicate that both antiparallel and parallel D23N-Aβ1–40 fibrils are cytotoxic. Thus, our antiparallel D23N-Aβ1–40 fibril model represents a specific “toxic intermediate” in the aggregation process of a disease-associated Aβ mutant.This publication has 53 references indexed in Scilit:
- The Core of Ure2p Prion Fibrils Is Formed by the N-Terminal Segment in a Parallel Cross-β Structure: Evidence from Solid-State NMRJournal of Molecular Biology, 2011
- Structural Evolution of Iowa Mutant β-Amyloid Fibrils from Polymorphic to Homogeneous States under Repeated Seeded GrowthJournal of the American Chemical Society, 2011
- Intermolecular Alignment in β2-Microglobulin Amyloid FibrilsJournal of the American Chemical Society, 2010
- The α-Helical C-Terminal Domain of Full-Length Recombinant PrP Converts to an In-Register Parallel β-Sheet Structure in PrP Fibrils: Evidence from Solid State Nuclear Magnetic ResonanceBiochemistry, 2010
- Aβ(1–40) Forms Five Distinct Amyloid Structures whose β-Sheet Contents and Fibril Stabilities Are CorrelatedJournal of Molecular Biology, 2010
- TALOS+: a hybrid method for predicting protein backbone torsion angles from NMR chemical shiftsJournal of Biomolecular NMR, 2009
- Evidence for Novel β-Sheet Structures in Iowa Mutant β-Amyloid FibrilsBiochemistry, 2009
- Peptide Conformation and Supramolecular Organization in Amylin Fibrils: Constraints from Solid-State NMRBiochemistry, 2007
- Experimental Constraints on Quaternary Structure in Alzheimer's β-Amyloid FibrilsBiochemistry, 2005
- Structure of the cross-β spine of amyloid-like fibrilsNature, 2005