A Self-Consistent Field Analysis of the Neurofilament Brush with Amino-Acid Resolution

Abstract

Using the numerical model of Scheutjens and Fleer we investigated, on a self-consistent field level, the equilibrium structure of the neurofilament brush formed by the projection domains of NF-H, NF-M, and NF-L proteins. Although the actual amino-acid sequences in the projection domains are coarse-grained, the different (realistic) solubilities of amino-acid residues and the specific distribution of its intrinsic charges inside the arms of the NF proteins are taken explicitly into account. We collect strong evidence that the electrostatic interactions are a dominant force that controls the NF brush structure. There exists a remarkable spatial separation of the H, M, and L tails. In a dephosphorylated NF we found confined and flowerlike conformations for the H and M projection domains, respectively. We demonstrate that the ionization of KSP repeats in NF proteins triggers a conformational transition in the H tail that leads to the expulsion of its terminal (KEP) domain to the periphery of the NF brush. We argue that the phosphorylation of the NF proteins in axons can both increase the interfilament distance and stabilize cross bridges between neurofilaments.

Stimuli-sensitive intrinsically disordered protein brushes

“…An analogous low-salt 'osmotic brush' regime was not observed at pH 2.4 due to the high baseline ionic strength. Importantly, this salt-responsiveness is consistent with recent theoretical/ computational descriptions of native NF sidearm domains as polyelectrolyte brushes 30,31 , and the high-resolution structural characterization of NF networks 32 . However, the low-salt osmotic brush regime has not been reported previously for NF assemblies.…”

Neurofilament sidearms modulate parallel and crossed-filament orientations inducing nematic to isotropic and re-entrant birefringent hydrogels

“…Future MD simulations of NF sidearm interactions as a function of varying ionic strength, taking into account the actual net charge and charge pattern in the sidearms 21,38 , is much needed to look for direct correlations between sidearm charge distribution pattern and the relative preference for the crossed versus parallel filaments orientations.…”

Conformational properties of interacting neurofilaments: Monte Carlo simulations of cylindrically grafted apposing neurofilament brushes

“…Upon phosphorylation, NF-H sidearms also become negatively charged polyampholytes due to the excess negative charges from the KSP phosphorylation. These behaviors inspired the treatment of NF sidearms as polyampholyte brushes in many recent studies [23][24][25].…”