On the Microtubule-Stabilizing Properties of a Tau Oligopeptide

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva


Preserving the integrity of neuronal microtubules (MTs) has emerged as a promising strategy to inhibit the progression of neurodegenerative disorders such as Alzheimer's disease. Such a goal could be achieved by peptides that mimic the functional role of Tau, an MT-associated protein that stabilizes MTs by dynamically binding to their outer surface. This work examines the binding properties and MT-stabilizing potential of a 27-amino acid Tau oligopeptide from 300 ns Gaussian-accelerated molecular dynamics simulations and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) calculations on octameric MT models bound to two equivalent and independent Tau peptides. Bound peptides adopted extended conformations that are highly consistent with cryo-electron microscopy reports for full-length Tau bound to MTs. Anchoring points in three consecutive tubulin subunits were identified, with a relevant contribution of the Ser419-Val435 region to α-tubulin. Tau peptides strengthen the longitudinal protein-protein contacts within the MT lattice and exert a cooperative MT-stabilizing effect in MT complexes simultaneously bonded to taxol or peloruside A. Ser phosphorylation results in a larger peptide mobility, altered interaction profiles, and MT destabilization, which are in line with the loss of MT integrity resulting from the post-translational hyperphosphorylation of Tau. Our results shed light on the MT-stabilizing potential of Tau-mimetic peptides to act as novel neuroprotective agents targeting MTs.

Idioma originalInglés
Páginas (desde-hasta)5682-5691
Número de páginas10
PublicaciónJournal of Chemical Information and Modeling
EstadoPublicada - 22 nov. 2021

Áreas temáticas de ASJC Scopus

  • Química (todo)
  • Ingeniería química (todo)
  • Informática aplicada
  • Biblioteconomía y ciencias de la información


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