On the Microtubule-Stabilizing Properties of a Tau Oligopeptide

• Published in: Journal of chemical information and modeling Vol. 61; no. 11; pp. 5682 - 5691
• Main Author: Jiménez, Verónica A
• Format: Journal Article
• Language: English
• Published: Washington American Chemical Society 22.11.2021
• Subjects: Alzheimer's disease; Amino acids; Binding; Destabilization; Integrity; Molecular dynamics; Peptides; Pharmaceutical Modeling; Phosphorylation; Proteins
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.1c00955

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.