High-resolution structure of monomorphic Aβ1-40 fibrils

• 成果类型: Article
• 署名作者: Bahri, Salima; Palani, Ravi Shankar; Silvers, Robert; Michael, Brian; Lattanzi, Veronica; Andre, Ingemar; Linse, Sara; Griffin, Robert G.
• 署名单位: Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); State University System of Florida; Florida State University; Lund University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2603575123
• 发表日期: 2026-07-14
• 页码: e2603575123
• 关键词: Alzheimer's disease; A beta 1-40; magic-angle spinning; nmr; fibril structure; BETA-AMYLOID FIBRILS; alzheimers-disease brain; SOLID-STATE; experimental constraints; a-beta; polymorphism; a-beta-40; proteins; aggregation; MODEL

摘要

Amyloid-beta (A beta) fibrils primarily composed of A beta 1-40 and A beta 1-42 form the core of senile plaques in Alzheimer's disease. A beta 1-40 fibrils may exhibit significant polymorphism influenced by sample preparation conditions, complicating atomic resolution structural characterization. To establish a reliable structural baseline, we developed a protocol for expressing and purifying recombinant A beta 1-40 that forms monomorphic fibrils under physiological conditions (pH 7.4). We present a high-resolution structure of these unseeded, monomorphic A beta 1-40 fibrils obtained using magic-angle spinning NMR spectroscopy (PDB ID 12GB). We obtained unambiguous chemical shift assignments for approximately 90% of the residues and measured over 500 distance and torsion angle restraints. The resolved structure, with a backbone RMSD of 0.63 +/- 0.06 & Aring;, shows two monomers per filament plane, with two distinct beta-sheets (residues E11-E22 and K28-V39, respectively) running along the fibril axis with H-bonding between each plane, and the two strands linked by a flexible loop region. This structure reveals three continuous hydrophobic cores inside each filament which bury 24 hydrophobic side chains per filament plane: those of L17, F19, A21, V24, A30, I32, M35, V40 between the two beta-strands within each monomer and I31, L34, V36, V39 between the two monomers. Small angle X-ray scattering reveals the size and geometry of the fibril cross-section, which is compatible with a two-filament arrangement with a total of 4 monomers per fibril plane.