Peptide dimer structure in an Aβ(1-42) fibril visualized with cryo-EM

Proceedings of the National Academy of Sciences of the United States of America
Matthias SchmidtNikolaus Grigorieff

Abstract

Alzheimer's disease (AD) is a fatal neurodegenerative disorder in humans and the main cause of dementia in aging societies. The disease is characterized by the aberrant formation of β-amyloid (Aβ) peptide oligomers and fibrils. These structures may damage the brain and give rise to cerebral amyloid angiopathy, neuronal dysfunction, and cellular toxicity. Although the connection between AD and Aβ fibrillation is extensively documented, much is still unknown about the formation of these Aβ aggregates and their structures at the molecular level. Here, we combined electron cryomicroscopy, 3D reconstruction, and integrative structural modeling methods to determine the molecular architecture of a fibril formed by Aβ(1-42), a particularly pathogenic variant of Aβ peptide. Our model reveals that the individual layers of the Aβ fibril are formed by peptide dimers with face-to-face packing. The two peptides forming the dimer possess identical tilde-shaped conformations and interact with each other by packing of their hydrophobic C-terminal β-strands. The peptide C termini are located close to the main fibril axis, where they produce a hydrophobic core and are surrounded by the structurally more flexible and charged segments of the peptid...Continue Reading

References

Aug 22, 1997·The Journal of Biological Chemistry·W Garzon-RodriguezC G Glabe
Dec 22, 1999·Journal of Structural Biology·S J LudtkeW Chiu
Jun 5, 2003·Journal of Structural Biology·Joseph A Mindell, Nikolaus Grigorieff
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Nov 19, 2005·Proceedings of the National Academy of Sciences of the United States of America·Thorsten LührsRoland Riek
Jan 25, 2007·Nature Reviews. Molecular Cell Biology·Christian Haass, Dennis J Selkoe
Feb 9, 2007·Journal of Neurochemistry·Dominic M Walsh, Dennis J Selkoe
Apr 13, 2007·Neuro-degenerative Diseases·Verena H Finder, Rudi Glockshuber
May 1, 2007·Nature·Michael R SawayaDavid Eisenberg
Jun 26, 2007·Journal of Molecular Biology·Carsten SachseNikolaus Grigorieff
Jan 16, 2008·Journal of Computational Chemistry·Piotr Rotkiewicz, Jeffrey Skolnick
May 17, 2008·Proceedings of the National Academy of Sciences of the United States of America·Carsten SachseNikolaus Grigorieff
Sep 10, 2008·Proceedings of the National Academy of Sciences of the United States of America·Erica A FradingerGal Bitan
Mar 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Rui ZhangJin-Moo Lee
Apr 7, 2009·Journal of Molecular Biology·Helen E WhiteHelen R Saibil
Sep 29, 2009·Journal of Molecular Biology·Thomas R JahnLouise C Serpell
Oct 22, 2009·Proceedings of the National Academy of Sciences of the United States of America·Matthias SchmidtNikolaus Grigorieff
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Feb 6, 2010·Proceedings of the National Academy of Sciences of the United States of America·Lukasz GoldschmidtDavid Eisenberg
Jan 12, 2011·Annual Review of Physical Chemistry·Robert Tycko
Mar 18, 2011·Trends in Biochemical Sciences·Marcus FändrichNikolaus Grigorieff
Sep 29, 2011·Proceedings of the National Academy of Sciences of the United States of America·Jacques-Philippe ColletierDavid Eisenberg
Dec 16, 2011·Proceedings of the National Academy of Sciences of the United States of America·Joseph M PerchiaccaPeter M Tessier
Jan 17, 2012·Journal of Molecular Biology·Torleif Härd, Christofer Lendel
May 9, 2012·Angewandte Chemie·Juan Miguel Lopez del AmoBernd Reif
Nov 17, 2012·Journal of Molecular Biology·Robin RoychaudhuriDavid B Teplow
Feb 22, 2013·ELife·Nikolaus Grigorieff
Mar 21, 2013·Proceedings of the National Academy of Sciences of the United States of America·Anthony W P FitzpatrickChristopher M Dobson
Mar 25, 2014·Journal of Structural Biology·Alexis Rohou, Nikolaus Grigorieff
May 24, 2014·Neuron·Tara L Spires-Jones, Bradley T Hyman

❮ Previous
Next ❯

Citations

Mar 2, 2016·Journal of Peptide Science : an Official Publication of the European Peptide Society·Vladimir TorbeevDonald Hilvert
Mar 24, 2016·Mechanisms of Ageing and Development·Bahareh EftekharzadehSusanne Wegmann
Apr 18, 2016·Journal of Trace Elements in Medicine and Biology : Organ of the Society for Minerals and Trace Elements (GMS)·Cecilia WallinSebastian K T S Wärmländer
May 4, 2016·Proceedings of the National Academy of Sciences of the United States of America·Marius KollmerMarcus Fändrich
Mar 15, 2016·Amyloid : the International Journal of Experimental and Clinical Investigation : the Official Journal of the International Society of Amyloidosis·Megan GarveyJochen Balbach
May 9, 2016·Journal of Biological Physics·Matjaž ŽganecBrigita Urbanc
Jun 4, 2016·Journal of Structural Biology·Nicolas CoudrayDavid L Stokes
Jun 30, 2016·Journal of the American Chemical Society·Michael T ColvinRobert G Griffin
Jul 28, 2016·The Journal of Chemical Physics·Mara ChiricottoFabio Sterpone
Jul 23, 2016·Scientific Reports·Karen E MarshallLouise C Serpell
Jul 30, 2016·Proceedings of the National Academy of Sciences of the United States of America·Marielle Aulikki WältiRoland Riek
Aug 11, 2016·Proceedings of the National Academy of Sciences of the United States of America·David S Eisenberg, Michael R Sawaya
Nov 9, 2016·Journal of the American Society for Mass Spectrometry·Xueqin PangLingjun Li
Dec 17, 2016·FEBS Letters·Joyce TranZhefeng Guo
Jan 31, 2017·ACS Chemical Neuroscience·Simona TomaselliLaura Ragona
Apr 28, 2017·Journal of the American Chemical Society·Kevin J DonovanRobert G Griffin
Mar 10, 2016·Angewandte Chemie·Karthikeyan AnnamalaiMarcus Fändrich
May 3, 2016·Chemistry : a European Journal·Bogdan Barz, Birgit Strodel
Jan 27, 2017·Annual Review of Biochemistry·David S Eisenberg, Michael R Sawaya
Nov 16, 2016·Molecular BioSystems·L Dorosh, M Stepanova
Jan 18, 2018·Nature Structural & Molecular Biology·Marcus Gallagher-JonesJose A Rodriguez
Feb 15, 2018·International Journal of Molecular Sciences·Gianvito GrassoMarco A Deriu
Mar 14, 2018·Nature Structural & Molecular Biology·Elizabeth L GuentherDavid S Eisenberg
May 8, 2018·Pathogens·José Miguel Flores-FernándezHolger Wille
Oct 13, 2017·Physical Chemistry Chemical Physics : PCCP·Adolfo B PomaMarek Cieplak
Jul 14, 2016·Physical Chemistry Chemical Physics : PCCP·Baiping RenJie Zheng
Jul 20, 2018·Chemical Communications : Chem Comm·Ling-Yu BaoZhi-Guo Gu
Nov 8, 2018·Biotechnic & Histochemistry : Official Publication of the Biological Stain Commission·Richard W Dapson
Mar 17, 2018·Biochemistry. Biokhimii︠a︡·O V GalzitskayaO M Selivanova
Feb 18, 2018·Nature Communications·William CloseMarcus Fändrich
Sep 9, 2017·Science·Lothar GremerGunnar F Schröder
Nov 11, 2016·Nature·Roland Riek, David S Eisenberg
Feb 21, 2018·Biomedit︠s︡inskai︠a︡ khimii︠a︡·O M SelivanovaO V Galzitskaya
Feb 11, 2020·Acta Crystallographica. Section D, Structural Biology·Biel Roig-SolvasLee Makowski
Apr 18, 2020·Chemical Communications : Chem Comm·Bikash R SahooAyyalusamy Ramamoorthy
May 20, 2020·Chembiochem : a European Journal of Chemical Biology·Jevgenij A Raskatov
May 23, 2020·Proceedings of the National Academy of Sciences of the United States of America·Mattias TörnquistSara Linse
Feb 25, 2017·Science·Einav Tayeb-FligelmanMeytal Landau

❮ Previous
Next ❯

Related Concepts

Related Feeds

Aging Epidemiology

This feed focuses on epidemiology of aging and aging-related conditions, including Alzheimer’s disease, dementia, and age-associated cognitive impairment. Here is the latest research.

Alzheimer's Disease: Amyloid Beta

Alzheimer's disease is a neurodegenerative disease associated with the accumulation of amyloid plaques in the brain; these plaques are comprised of amyloid beta deposits. Here is the latest research in this field.

Alzheimer's Disease: APP

Amyloid precursor protein (APP) proteolysis is critical for the development of Alzheimer's disease, a neurodegenerative disease associated with accumulation of amyloid plaques in the brain. Here is the latest research on APP and Alzheimer's disease.

Age-related Dementia

Dementias are a group of conditions, including Alzheimer's disease, vascular dementia, and frontotemporal dementia, characterized by deficiencies in cognitive abilities. Age-related dementia refers to dementias that occur in older individuals, usually 60+ years old, in contrast to early-onset dementia. Follow the latest research on age-related dementia here.

Brain Aging

Here is the latest research on intrinsic and extrinsic factors, as well as pathways and mechanisms that underlie aging in the central nervous system.

Cell Aging (Keystone)

This feed focuses on cellular aging with emphasis on the mitochondria, autophagy, and metabolic processes associated with aging and longevity. Here is the latest research on cell aging.