Partial Mimicry of the Microtubule Binding of Tau by Its Membrane Binding

Abstract

Tau, as typical of intrinsically disordered proteins (IDPs), binds to multiple targets including microtubules and acidic membranes. The latter two surfaces are both highly negatively charged, raising the prospect of mimicry in their binding by tau. The tau-microtubule complex was recently determined by cryo-EM. Here we used molecular dynamics simulations to characterize the dynamic binding of tau K19 to an acidic membrane. This IDP can be divided into three repeats, each containing an amphipathic helix. The three amphipathic helices, along with flanking residues, tether the protein to the membrane interface. The separation between and membrane positioning of the amphipathic helices in the simulations are validated by published EPR data. The membrane contact probabilities of individual residues in tau show both similarities to and distinctions from native contacts with microtubules. In particular, a Lys that is conserved among the repeats forms similar interactions with membranes and with microtubules, as does a conserved Val. This partial mimicry facilitates both the membrane anchoring of microtubules by tau and the transfer of tau from membranes to microtubules.

Why Does Synergistic Activation of WASP, but Not N-WASP, by Cdc42 and PIP2Require Cdc42 Prenylation?

“…Binding studies [20] have shown that the N-WASP BR binds multiple PIP2 molecules and it is the number of basic residues, not the precise sequence, that determines the PIP2 binding affinity, typical of IDP binding to acidic membranes [30]. Structural characterization of IDP-membrane binding, due to its dynamic nature, presents challenges for experimental techniques, but this problem can now be addressed by molecular dynamics (MD) simulations [31][32][33][34].…”