Molecular Basis for Neurofilament Heavy Chain Side Arm Structure Modulation by Phosphorylation

作者：Adiga Shashishekar P^*; Brenner Donald W

来源：Journal of Physical Chemistry C, 2010, 114(12): 5410-5416.

DOI：10.1021/jp905671u

The role of phosphorylation of neurofilament side arms in neurofilament transport and in several neuromuscular diseases is a topic of active research. However, owing to the lack of a secondary structure of the side arms, little is known about the precise nature of the structural modifications caused by this important post-translational modification. Here, we probe the effect of phosphorylation on the structure of the C-terminal domain of the human neurofilament heavy chain NFH using molecular dynamics simulations. Our study indicates that the unphosphorylated NFH side arm is unstructured and characterized by several flexible loops stabilized by salt bridges. Phosphorylation of multiple SER residues is shown to destabilize these bridges due to electrostatic repulsion and thereby increase side arm sire. We demonstrate that phosphorylation acts locally by modulating intramolecular electrostatic interactions to cause global changes in the otherwise disordered side arm. Our findings have implications for understanding the functioning of neurofilaments in health and disease.

• 出版日期2010-4-1