Expanded Conformations of Monomeric Tau Initiate Its Amyloidogenesis

Autor: María del Carmen Fernández‐Ramírez, Kevin Kan‐Shing Ng, Margarita Menéndez, Douglas V. Laurents, Rubén Hervás, Mariano Carrión‐Vázquez
Přispěvatelé: Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España)
Rok vydání: 2022
Předmět:
Zdroj: Angewandte Chemie (International ed. in English).
ISSN: 1521-3773
Popis: 11 pags., 5 figs.
Understanding early amyloidogenesis is key to rationally develop therapeutic strategies. Tau protein forms well-characterized pathological deposits but its aggregation mechanism is still poorly understood. Using single-molecule force spectroscopy based on a mechanical protection strategy, we studied the conformational landscape of the monomeric tau repeat domain (tauRD244-368). We found two sets of conformational states, whose frequency is influenced by mutations and the chemical context. While pathological mutations Δ280K and P301L and a pro-amyloidogenic milieu favored expanded conformations and destabilized local structures, an anti-amyloidogenic environment promoted a compact ensemble, including a conformer whose topology might mask two amyloidogenic segments. Our results reveal that to initiate aggregation, monomeric tau-RD244-368 decreases its polymorphism adopting expanded conformations. This could account for the distinct structures found in vitro and across tauopathies.
Spanish Agency for Research (AEI). Grant Numbers: SAF2016-76678-C2-1-R, SAF2016-76678-C2-2-R, BFU2015-70072-R
Databáze: OpenAIRE
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