Cargando…

Arginine π-stacking drives binding to fibrils of the Alzheimer protein Tau

Aggregation of the Tau protein into fibrils defines progression of neurodegenerative diseases, including Alzheimer’s Disease. The molecular basis for potentially toxic reactions of Tau aggregates is poorly understood. Here we show that π-stacking by Arginine side-chains drives protein binding to Tau...

Descripción completa

Detalles Bibliográficos
Autores principales: Ferrari, Luca, Stucchi, Riccardo, Konstantoulea, Katerina, van de Kamp, Gerarda, Kos, Renate, Geerts, Willie J. C., van Bezouwen, Laura S., Förster, Friedrich G., Altelaar, Maarten, Hoogenraad, Casper C., Rüdiger, Stefan G. D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989696/
https://www.ncbi.nlm.nih.gov/pubmed/31996674
http://dx.doi.org/10.1038/s41467-019-13745-7
_version_ 1783492457947725824
author Ferrari, Luca
Stucchi, Riccardo
Konstantoulea, Katerina
van de Kamp, Gerarda
Kos, Renate
Geerts, Willie J. C.
van Bezouwen, Laura S.
Förster, Friedrich G.
Altelaar, Maarten
Hoogenraad, Casper C.
Rüdiger, Stefan G. D.
author_facet Ferrari, Luca
Stucchi, Riccardo
Konstantoulea, Katerina
van de Kamp, Gerarda
Kos, Renate
Geerts, Willie J. C.
van Bezouwen, Laura S.
Förster, Friedrich G.
Altelaar, Maarten
Hoogenraad, Casper C.
Rüdiger, Stefan G. D.
author_sort Ferrari, Luca
collection PubMed
description Aggregation of the Tau protein into fibrils defines progression of neurodegenerative diseases, including Alzheimer’s Disease. The molecular basis for potentially toxic reactions of Tau aggregates is poorly understood. Here we show that π-stacking by Arginine side-chains drives protein binding to Tau fibrils. We mapped an aggregation-dependent interaction pattern of Tau. Fibrils recruit specifically aberrant interactors characterised by intrinsically disordered regions of atypical sequence features. Arginine residues are key to initiate these aberrant interactions. Crucial for scavenging is the guanidinium group of its side chain, not its charge, indicating a key role of π-stacking chemistry for driving aberrant fibril interactions. Remarkably, despite the non-hydrophobic interaction mode, the molecular chaperone Hsp90 can modulate aberrant fibril binding. Together, our data present a molecular mode of action for derailment of protein-protein interaction by neurotoxic fibrils.
format Online
Article
Text
id pubmed-6989696
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-69896962020-01-31 Arginine π-stacking drives binding to fibrils of the Alzheimer protein Tau Ferrari, Luca Stucchi, Riccardo Konstantoulea, Katerina van de Kamp, Gerarda Kos, Renate Geerts, Willie J. C. van Bezouwen, Laura S. Förster, Friedrich G. Altelaar, Maarten Hoogenraad, Casper C. Rüdiger, Stefan G. D. Nat Commun Article Aggregation of the Tau protein into fibrils defines progression of neurodegenerative diseases, including Alzheimer’s Disease. The molecular basis for potentially toxic reactions of Tau aggregates is poorly understood. Here we show that π-stacking by Arginine side-chains drives protein binding to Tau fibrils. We mapped an aggregation-dependent interaction pattern of Tau. Fibrils recruit specifically aberrant interactors characterised by intrinsically disordered regions of atypical sequence features. Arginine residues are key to initiate these aberrant interactions. Crucial for scavenging is the guanidinium group of its side chain, not its charge, indicating a key role of π-stacking chemistry for driving aberrant fibril interactions. Remarkably, despite the non-hydrophobic interaction mode, the molecular chaperone Hsp90 can modulate aberrant fibril binding. Together, our data present a molecular mode of action for derailment of protein-protein interaction by neurotoxic fibrils. Nature Publishing Group UK 2020-01-29 /pmc/articles/PMC6989696/ /pubmed/31996674 http://dx.doi.org/10.1038/s41467-019-13745-7 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Ferrari, Luca
Stucchi, Riccardo
Konstantoulea, Katerina
van de Kamp, Gerarda
Kos, Renate
Geerts, Willie J. C.
van Bezouwen, Laura S.
Förster, Friedrich G.
Altelaar, Maarten
Hoogenraad, Casper C.
Rüdiger, Stefan G. D.
Arginine π-stacking drives binding to fibrils of the Alzheimer protein Tau
title Arginine π-stacking drives binding to fibrils of the Alzheimer protein Tau
title_full Arginine π-stacking drives binding to fibrils of the Alzheimer protein Tau
title_fullStr Arginine π-stacking drives binding to fibrils of the Alzheimer protein Tau
title_full_unstemmed Arginine π-stacking drives binding to fibrils of the Alzheimer protein Tau
title_short Arginine π-stacking drives binding to fibrils of the Alzheimer protein Tau
title_sort arginine π-stacking drives binding to fibrils of the alzheimer protein tau
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989696/
https://www.ncbi.nlm.nih.gov/pubmed/31996674
http://dx.doi.org/10.1038/s41467-019-13745-7
work_keys_str_mv AT ferrariluca argininepstackingdrivesbindingtofibrilsofthealzheimerproteintau
AT stucchiriccardo argininepstackingdrivesbindingtofibrilsofthealzheimerproteintau
AT konstantouleakaterina argininepstackingdrivesbindingtofibrilsofthealzheimerproteintau
AT vandekampgerarda argininepstackingdrivesbindingtofibrilsofthealzheimerproteintau
AT kosrenate argininepstackingdrivesbindingtofibrilsofthealzheimerproteintau
AT geertswilliejc argininepstackingdrivesbindingtofibrilsofthealzheimerproteintau
AT vanbezouwenlauras argininepstackingdrivesbindingtofibrilsofthealzheimerproteintau
AT forsterfriedrichg argininepstackingdrivesbindingtofibrilsofthealzheimerproteintau
AT altelaarmaarten argininepstackingdrivesbindingtofibrilsofthealzheimerproteintau
AT hoogenraadcasperc argininepstackingdrivesbindingtofibrilsofthealzheimerproteintau
AT rudigerstefangd argininepstackingdrivesbindingtofibrilsofthealzheimerproteintau