Fibril structure of amyloid-ß(1-42) by cryo-electron microscopy
By L. Gremer, Daniel Schölzel, Carla Schenk, Elke Reinartz, J. Labahn, R. Ravelli, Markus Tusche, C. López-Iglesias, W. Hoyer, H. Heise and 2 more. Science, 2017
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Elucidating pathological fibril structure Amyloid-β (Aβ) is a key pathological contributor to Alzheimer's disease. Gremer et al. used cryoelectron microscopy data to build a high-quality de novo atomic model of Aβ fibrils (see the Perspective by Pospich and Raunser). The complete structure reveals all 42 amino acids (including the entire N terminus) and provides a structural basis for understanding the effect of several disease-causing and disease-preventing mutations. The fibril consists of two intertwined protofilaments with an unexpected dimer interface that is different from those proposed previously. The structure has implications for the mechanism of fibril growth and will be an important stepping stone to rational drug design. Science, this issue p. 116; see also p. 45 Cryo–electron microscopy structure of an amyloid-β(1–42) fibril reveals a protofilament interface and the entire N-terminal region. Amyloids are implicated in neurodegenerative diseases. Fibrillar aggregates of the amyloid-β protein (Aβ) are the main component of the senile plaques found in brains of Alzheimer’s disease patients. We present the structure of an Aβ(1–42) fibril composed of two intertwined protofilaments determined by cryo–electron microscopy (cryo-EM) to 4.0-angstrom resolution, complemented by solid-state nuclear magnetic resonance experiments. The backbone of all 42 residues and nearly all side chains are well resolved in the EM density map, including the entire N terminus, which is part of the cross-β structure resulting in an overall “LS”-shaped topology of individual subunits. The dimer interface protects the hydrophobic C termini from the solvent. The characteristic staggering of the nonplanar subunits results in markedly different fibril ends, termed “groove” and “ridge,” leading to different binding pathways on both fibril ends, which has implications for fibril growth.
Subfields: Materials Chemistry, Molecular Biology, Physiology
View Paper: https://www.semanticscholar.org/paper/e9fe9d4b8396e603dab24ca7638d02f783041f78
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Citations in the corpus
- Advances in methods for atomic resolution macromolecular structure determination (2020, background): “Of particular interest in medicine, amyloid proteins and polypeptides, which assemble in ways that tend to be incommensurate with three-dimensional crystal formation, have been analyzed recently by cryo-EM, with numerous studies reaching near-atomic resolution 35–42 .”
- Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019, positive): “Recent cryo-EM experiments have elucidated the structure of synthetically-derived Aβ42 fibrils, demonstrating 7 nm diameter fibrils containing two twisted protofilaments consisting of Aβ42 monomers assuming a “LS” shape stacked in parallel with in-register cross-β structure (Gremer et al., 2017).”