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Fibril structure of amyloid-β(1–42) by cryo–electron microscopy

2017; American Association for the Advancement of Science; Volume: 358; Issue: 6359 Linguagem: Inglês

10.1126/science.aao2825

1095-9203

Lothar Gremer, Daniel Schölzel, C. Schenk, Elke Reinartz, Jörg Labahn, Raimond B. G. Ravelli, Markus Tusche, Carmen López‐Iglesias, Wolfgang Hoyer, Henrike Heise, Dieter Willbold, Gunnar F. Schröder,

Enzyme Structure and Function

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.