On the Microtubule-Stabilizing Properties of a Tau Oligopeptide

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.