Structural and mechanistic basis behind the inhibitory interaction of PcTS on alpha-synuclein amyloid fibril formation.

Proceedings of the National Academy of Sciences of the United States of America
Gonzalo R LambertoClaudio O Fernández

Abstract

The identification of aggregation inhibitors and the investigation of their mechanism of action are fundamental in the quest to mitigate the pathological consequences of amyloid formation. Here, characterization of the structural and mechanistic basis for the antiamyloidogenic effect of phthalocyanine tetrasulfonate (PcTS) on alpha-synuclein (AS) allowed us to demonstrate that specific aromatic interactions are central for ligand-mediated inhibition of amyloid formation. We provide evidence indicating that the mechanism behind the antiamyloidogenic effect of PcTS is correlated with the trapping of prefibrillar AS species during the early stages of the assembly process. By using NMR spectroscopy, we have located the primary binding region for PcTS to a specific site in the N terminus of AS, involving the amino acid Tyr-39 as the anchoring residue. Moreover, the residue-specific structural characterization of the AS-PcTS complex provided the basis for the rational design of nonamyloidogenic species of AS, highlighting the role of aromatic interactions in driving AS amyloid assembly. A comparative analysis with other proteins involved in neurodegenerative disorders reveals that aromatic recognition interfaces might constitute a ke...Continue Reading

References

Nov 1, 1995·Journal of Biomolecular NMR·F DelaglioA Bax
Aug 28, 1997·Nature·M G SpillantiniM Goedert
Dec 12, 1997·FEBS Letters·D HowlettP Camilleri
Oct 15, 1998·Proceedings of the National Academy of Sciences of the United States of America·W S CaugheyB Caughey
Apr 23, 1999·The Journal of Biological Chemistry·L O TjernbergC Nordstedt
Feb 26, 2000·Science·S A PriolaW S Caughey
May 11, 2000·Proceedings of the National Academy of Sciences of the United States of America·M von BergenE Mandelkow
Jun 20, 2003·The Journal of Biological Chemistry·Ani Der-SarkissianRalf Langen
Dec 31, 2003·The Journal of Biological Chemistry·Wenbo Zhou, Curt R Freed
Apr 21, 2004·The Journal of Biological Chemistry·Min ZhuAnthony L Fink
May 4, 2004·Journal of Peptide Science : an Official Publication of the European Peptide Society·Shenggen YaoKevin J Barnham
Dec 22, 2004·The Journal of Biological Chemistry·Sayuri TaniguchiMasato Hasegawa
Jan 27, 2005·Proceedings of the National Academy of Sciences of the United States of America·Carlos W BertonciniMarkus Zweckstetter
Apr 9, 2005·The Journal of Biological Chemistry·Erin H NorrisVirginia M-Y Lee
Oct 26, 2005·Proceedings of the National Academy of Sciences of the United States of America·Henrike HeiseMarc Baldus
Nov 25, 2005·Journal of the American Chemical Society·Jennifer C LeeJay R Winkler
May 10, 2006·Biochemistry·Masami MasudaMasato Hasegawa
Feb 7, 2007·The Journal of Physical Chemistry. B·Jennifer C LeeJay R Winkler
Jun 19, 2007·The Journal of Biological Chemistry·Min ChenRalf Langen
Oct 11, 2007·Proceedings of the National Academy of Sciences of the United States of America·Vanita ChopraSteven Hersch
Feb 26, 2008·Current Opinion in Chemical Biology·Leila M LuheshiChristopher M Dobson
May 31, 2008·Nature Structural & Molecular Biology·Dagmar E EhrnhoeferErich E Wanker
Jun 14, 2008·Proceedings of the National Academy of Sciences of the United States of America·Marçal VilarRoland Riek
Aug 12, 2008·Biochimica Et Biophysica Acta·Natasa Poklar UlrihAnthony L Fink
Sep 9, 2008·Journal of Molecular Biology·Dong-Pyo HongVladimir N Uversky

❮ Previous
Next ❯

Citations

Feb 26, 2014·Bioorganic & Medicinal Chemistry·Vladyslava B KovalskaSergiy V Volkov
May 25, 2012·Biochemistry·Irina SurguchevaAndrei Surguchov
Mar 21, 2013·ACS Chemical Neuroscience·Pradeep K SinghSamir K Maji
Jan 31, 2013·Journal of the American Chemical Society·Elias AkouryMarkus Zweckstetter
Jul 29, 2011·The Journal of Biological Chemistry·Gonzalo R LambertoClaudio O Fernández
Jan 24, 2012·The Journal of Biological Chemistry·Basir Ahmad, Lisa J Lapidus
Oct 22, 2014·Protein Engineering, Design & Selection : PEDS·Aziz GauharWolfgang Hoyer
Sep 7, 2013·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Simone KosolPeter Tompa
Jan 26, 2016·Nature·Francois-Xavier TheilletPhilipp Selenko
Apr 7, 2012·Biochimica Et Biophysica Acta·Derek R DeeMichael T Woodside
Sep 20, 2012·Biochemical Society Transactions·Andres BinolfiPhilipp Selenko
Feb 10, 2012·The Biochemical Journal·María Soledad CelejVincent Raussens
Mar 13, 2012·Biophysical Journal·Jonathan A FauerbachElizabeth A Jares-Erijman
May 3, 2016·Accounts of Chemical Research·Ariel A Valiente-GabioudClaudio O Fernández
Sep 10, 2013·Biophysical Journal·Santiago Esteban-MartínXavier Salvatella
Sep 1, 2017·Journal of Molecular Recognition : JMR·V KovalskaS Yarmoluk
Dec 8, 2017·Cell Biology and Toxicology·Wenbo YuBaoguo Xiao
Oct 20, 2012·Protein Science : a Publication of the Protein Society·Yuji O KamatariKazuo Kuwata
Apr 17, 2012·Chembiochem : a European Journal of Chemical Biology·Nasrollah Rezaei-GhalehMarkus Zweckstetter
Jun 28, 2016·Nature Communications·Amar Nath GuptaMichael T Woodside
Sep 28, 2013·The Journal of Biological Chemistry·Kelsey N SchaferJeff Kuret
Jul 16, 2019·Protein Science : a Publication of the Protein Society·Chunhua DongMichael T Woodside
Sep 6, 2019·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Nazareno GonzálezClaudio O Fernández
Oct 6, 2019·Acta Pharmacologica Sinica·Ming-Ming XuGeorge D Mellick
Aug 22, 2014·The Journal of Biological Chemistry·J Ignacio Gallea, M Soledad Celej
Apr 7, 2018·Chemistry : a European Journal·Valentina OliveriGraziella Vecchio
Aug 2, 2017·Chemistry : a European Journal·Luis Fonseca-OrnelasMarkus Zweckstetter
Aug 16, 2018·Acta Neuropathologica Communications·Caterina MasaracchiaTiago F Outeiro
Jul 28, 2020·International Journal of Molecular Sciences·Oscar Palomino-HernandezClaudio O Fernandez
Jul 27, 2012·Journal of Inorganic Biochemistry·Ariel A Valiente-GabioudClaudio O Fernández
Jul 28, 2021·NPJ Parkinson's Disease·Luis M A OliveiraTiago F Outeiro
Jun 6, 2014·Chemical Reviews·Francois-Xavier TheilletPhilipp Selenko

❮ Previous
Next ❯

Related Concepts

Related Feeds

Alpha-Synuclein Aggregation (MDS)

Alpha-synucleins are small proteins that are believed to restrict the mobility of synpatic vesicles and inhibit neurotransmitter release. Aggregation of these proteins have been linked to several types of neurodegenerative diseases including dementia with Lewy bodies and Parkinson's disease. Here is the latest research on α-synuclein aggregation.

Alpha-Synuclein Aggregation

Alpha-synucleins are small proteins that are believed to restrict the mobility of synpatic vesicles and inhibit neurotransmitter release. Aggregation of these proteins have been linked to several types of neurodegenerative diseases including dementia with Lewy bodies and Parkinson's disease. Here is the latest research on α-synuclein aggregation.