Phosphorylation-induced mechanical regulation of intrinsically disordered neurofilament protein assemblies

TL;DR

This study reveals how phosphorylation modulates the physical properties of neurofilament protein assemblies by altering electrostatic interactions, highlighting a complex regulatory mechanism beyond traditional structural roles.

Contribution

It demonstrates enzymatic phosphorylation as a key regulator of neurofilament network properties, expanding understanding of disordered protein assembly regulation.

Findings

Phosphorylation affects neurofilament network orientation and stress response.

Enzymatic charge regulation influences macroscopic properties of protein assemblies.

A model explains electrostatic interactions induced by phosphorylation.

Abstract

The biological function of protein assemblies was conventionally equated with a unique three-dimensional protein structure and protein-specific interactions. However, in the past 20 years it was found that some assemblies contain long flexible regions that adopt multiple structural conformations. These include neurofilament (NF) proteins that constitute the stress-responsive supportive network of neurons. Herein, we show that NF networks macroscopic properties are tuned by enzymatic regulation of the charge found on the flexible protein regions. The results reveal an enzymatic (phosphorylation) regulation of macroscopic properties such as orientation, stress-response and expansion in flexible protein assemblies. Together with a model explaining the attractive electrostatic interactions induced by enzymatically added charges, we demonstrate that phosphorylation-regulation is far richer and versatile than previously considered.