A new structural model of Alzheimer's Aβ42 fibrils based on electron paramagnetic resonance data and Rosetta modeling

Journal of Structural Biology
Lei GuZhefeng Guo

Abstract

Brain deposition of Aβ in the form of amyloid plaques is a pathological hallmark of Alzheimer's disease. There are two major species of Aβ in the brain: Aβ42 and Aβ40. Although Aβ40 is several-fold more abundant than Aβ42 in soluble form, Aβ42 is the major component of amyloid plaques. Structural knowledge of Aβ42 fibrils is important both for understanding the process of Aβ aggregation and for designing fibril-targeting drugs. Here we report site-specific structural information of Aβ42 fibrils at 22 residue positions based on electron paramagnetic resonance data. In combination with structure prediction program Rosetta, we modeled Aβ42 fibril structure at atomic resolution. Our Aβ42 fibril model consists of four parallel in-register β-sheets: βN (residues ∼7-13), β1 (residues ∼17-20), β2 (residues ∼32-36), and βC (residues 39-41). The region of β1-loop-β2 in Aβ42 fibrils adopts similar structure as that in Aβ40 fibrils. This is consistent with our cross seeding data that Aβ42 fibril seeds shortened the lag phase of Aβ40 fibrillization. On the other hand, Aβ42 fibrils contain a C-terminal β-arc-β motif with a special turn, termed "arc", at residues 37-38, which is absent in Aβ40 fibrils. Our results can explain both the higher ...Continue Reading

References

Nov 25, 2003·Science·Brian KuhlmanDavid Baker
Oct 2, 2004·The Journal of Biological Chemistry·Akira MorimotoTakuji Shirasawa
Apr 4, 2006·Journal of Molecular Biology·Jérôme HennetinAndrey V Kajava
Jun 15, 2006·Quarterly Reviews of Biophysics·Robert Tycko
May 8, 2007·Journal of Molecular Biology·Yilin Yan, Chunyu Wang
Nov 6, 2007·Proceedings of the National Academy of Sciences of the United States of America·Ingemar AndréDavid Baker
Jul 7, 2011·The Journal of Biological Chemistry·Sam NgoZhefeng Guo
Oct 12, 2011·Biochemical and Biophysical Research Communications·Sam Ngo, Zhefeng Guo
Sep 10, 2015·Proceedings of the National Academy of Sciences of the United States of America·Matthias SchmidtNikolaus Grigorieff

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Citations

Nov 20, 2016·The Veterinary Record·Camilla Benfield
Dec 17, 2016·FEBS Letters·Joyce TranZhefeng Guo
Feb 15, 2018·International Journal of Molecular Sciences·Gianvito GrassoMarco A Deriu
Jul 9, 2020·Nanoscale·Nicholas AndrikopoulosPu Chun Ke
Aug 16, 2018·Royal Society Open Science·Hongsu WangZhefeng Guo
Jun 26, 2020·Frontiers in Immunology·Jelena MilovanovicNebojsa Arsenijevic
May 21, 2019·Frontiers in Bioengineering and Biotechnology·Gianvito GrassoMarco A Deriu
Mar 11, 2017·Biometals : an International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine·Foozhan Tahmasebinia, Saeed Emadi
Jul 28, 2017·Scientific Reports·Wenhui Xi, Ulrich H E Hansmann
Apr 11, 2020·International Journal of Molecular Sciences·Kai-Cyuan HeTa-Hsien Lin
Apr 14, 2020·Biological Trace Element Research·Yuichi SatoAtsushi Takeda
Jul 14, 2020·Frontiers in Bioengineering and Biotechnology·Konda Mani SaravananYanjie Wei
Aug 6, 2020·International Journal of Molecular Sciences·Francesco TavantiMaria Cristina Menziani
Feb 7, 2021·Biochemical and Biophysical Research Communications·Allison YoonZhefeng Guo
Apr 17, 2021·Biochemical and Biophysical Research Communications·Lei Gu, Zhefeng Guo
May 8, 2021·Royal Society Open Science·Emilie N LiuZhefeng Guo
Jul 17, 2021·International Journal of Biological Macromolecules·Parveen SalahuddinMunazza Tamkeen Fatima
Jan 23, 2018·Journal of Chemical Theory and Computation·Wenhui XiUlrich H E Hansmann
Aug 9, 2018·ACS Omega·Frederick HsuZhefeng Guo
Jan 29, 2017·The Journal of Physical Chemistry. B·Zhiguang JiaJeremy D Schmit
Aug 2, 2017·ACS Chemical Neuroscience·Witold Gospodarczyk, Maciej Kozak
Jan 13, 2018·Molecular Pharmaceutics·Roberta GiampietroNicola Antonio Colabufo

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