Inhibitors of amyloid toxicity based on beta-sheet packing of Abeta40 and Abeta42.

Biochemistry
Takeshi SatoSteven O Smith

Abstract

Amyloid fibrils associated with Alzheimer's disease and a wide range of other neurodegenerative diseases have a cross beta-sheet structure, where main chain hydrogen bonding occurs between beta-strands in the direction of the fibril axis. The surface of the beta-sheet has pronounced ridges and grooves when the individual beta-strands have a parallel orientation and the amino acids are in-register with one another. Here we show that in Abeta amyloid fibrils, Met35 packs against Gly33 in the C-terminus of Abeta40 and against Gly37 in the C-terminus of Abeta42. These packing interactions suggest that the protofilament subunits are displaced relative to one another in the Abeta40 and Abeta42 fibril structures. We take advantage of this corrugated structure to design a new class of inhibitors that prevent fibril formation by placing alternating glycine and aromatic residues on one face of a beta-strand. We show that peptide inhibitors based on a GxFxGxF framework disrupt sheet-to-sheet packing and inhibit the formation of mature Abeta fibrils as assayed by thioflavin T fluorescence, electron microscopy, and solid-state NMR spectroscopy. The alternating large and small amino acids in the GxFxGxF sequence are complementary to the corr...Continue Reading

References

Jan 1, 1986·Proceedings of the National Academy of Sciences of the United States of America·D A KirschnerD J Selkoe
Apr 12, 1996·The Journal of Biological Chemistry·L O TjernbergC Nordstedt
Sep 24, 1996·Biochemical and Biophysical Research Communications·C SotoB Frangione
Sep 20, 1996·Journal of Molecular Biology·L WangJ Hermans
Apr 1, 1997·Trends in Neurosciences·J Hardy
May 9, 1997·The Journal of Biological Chemistry·L O TjernbergC Nordstedt
Oct 6, 1998·Annual Review of Biochemistry·F E Cohen, S B Prusiner
Nov 13, 1998·Proceedings of the National Academy of Sciences of the United States of America·T L BenzingerS C Meredith
Mar 15, 2000·Journal of Molecular Biology·W P Russ, D M Engelman
Nov 9, 2000·Proceedings of the National Academy of Sciences of the United States of America·O N AntzutkinR Tycko
Sep 27, 2001·Proceedings of the National Academy of Sciences of the United States of America·D J Selkoe
Feb 28, 2002·The Journal of Biological Chemistry·Pascal Kienlen-CampardJean-Noël Octave
Apr 20, 2002·Biophysical Journal·Markus EilersSteven O Smith
Aug 29, 2002·The Journal of Biological Chemistry·Liming HouMichael G Zagorski
Dec 14, 2002·Proceedings of the National Academy of Sciences of the United States of America·Aneta T PetkovaRobert Tycko
Feb 13, 2003·The Journal of Biological Chemistry·Céline AdessiClaudio Soto
Jul 4, 2003·The Journal of Biological Chemistry·Robert J ChalifourFrancine Gervais
Dec 11, 2003·Journal of the American Chemical Society·Gal BitanDavid B Teplow
Dec 23, 2003·Journal of Molecular Biology·Angela D WilliamsRonald Wetzel
Jan 13, 2004·Proceedings of the National Academy of Sciences of the United States of America·Christopher P JaroniecRobert G Griffin
Mar 3, 2004·Journal of Neuroscience Research·Kenjiro OnoMasahito Yamada
Mar 16, 2004·Journal of Biomolecular NMR·Evan CrockerSteven O Smith
Apr 23, 2004·Current Opinion in Structural Biology·Robert Tycko
Jul 31, 2004·Methods : a Companion to Methods in Enzymology·Melanie R Nilsson
Aug 5, 2004·The Journal of Biological Chemistry·Giuseppe D CiccotostoKevin J Barnham

❮ Previous
Next ❯

Citations

Nov 16, 2007·European Biophysics Journal : EBJ·Victor Streltsov
Nov 13, 2009·Journal of Molecular Modeling·Kristin KasslerHeinrich Sticht
Apr 27, 2013·Journal of Bioenergetics and Biomembranes·Daniela MeleleoGabriella Notarachille
May 25, 2012·Neuroscience Bulletin·Bin YangYan Zhang
Jun 29, 2007·Expert Reviews in Molecular Medicine·Jean-Christophe Rochet
Nov 10, 2010·Biochemistry·Mukesh MaheshwariIan V J Murray
Feb 13, 2013·ACS Chemical Neuroscience·Matthew S PlanchardVijayaraghavan Rangachari
Feb 9, 2011·Journal of the American Chemical Society·Yifat MillerRuth Nussinov
Sep 3, 2011·Journal of the American Chemical Society·Ivano BertiniAntonella Nesi
May 1, 2013·Journal of the American Chemical Society·Wei QiangRobert Tycko
May 7, 2008·The Journal of Physical Chemistry. B·Jie ZhengRuth Nussinov
Jun 13, 2008·Nature·Thomas L KukarTodd E Golde
Apr 13, 2010·Nature Structural & Molecular Biology·Mahiuddin AhmedSteven O Smith
Apr 15, 2008·Proceedings of the National Academy of Sciences of the United States of America·Andrij BaumketnerJoan-Emma Shea
Mar 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Rui ZhangJin-Moo Lee
Oct 22, 2009·Proceedings of the National Academy of Sciences of the United States of America·Matthias SchmidtNikolaus Grigorieff
Mar 30, 2010·The Journal of Biological Chemistry·Richard M PageHarald Steiner
Dec 26, 2008·Journal of Biomolecular Structure & Dynamics·Jian-Hua ZhaoWei-Bor Tsai
May 19, 2010·Journal of Biomolecular Structure & Dynamics·Liang-Kai ChangYih Ho
Sep 4, 2013·Philosophical Transactions. Series A, Mathematical, Physical, and Engineering Sciences·Yanlian Yang, Chen Wang
Sep 22, 2009·Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire·Pharhad Eli Arslan, Avijit Chakrabartty
Jun 21, 2011·PloS One·Xiang Yu, Jie Zheng
Jun 6, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Jungsu KimTodd E Golde
Aug 3, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Roger LefortMichael Shelanski
Aug 20, 2009·Chemical Society Reviews·Arvi Rauk
Jun 8, 2012·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Olivia Wise-SciraOrkid Coskuner
Feb 4, 2012·Journal of Molecular Biology·Juan Miguel Lopez del AmoBernd Reif
Sep 20, 2011·Bioorganic & Medicinal Chemistry·Yuichi MasudaK Takegoshi

❮ Previous
Next ❯

Related Concepts

Related Feeds

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.

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.

© 2022 Meta ULC. All rights reserved