A systems biology approach for bio-molecular interactions within the Axon Initial Segment: A thesis submitted in partial fulfilment of the requirements for the Degree of Master of Science at Lincoln University

Abstract

The axon initial segment (AIS) region is crucial for action potential initiation due to the presence of high density voltage gated sodium channels (Nav). Nav channels consist of an AIS motif, with several serine residues responsible for the recruitment of Nav channels into the structure of AIS through interactions with ankyrin-G (AnkG). In this study, a series of computational experiments were conducted to understand the impact of serine-specific phosphorylation on Nav-AnkG binding. The simulation results indicate that Nav channels, with all serine sites available for phosphorylation, bind to AnkG with a strong affinity. Moreover, according to the mutational experiment in this study, the initial concentration of AnkG is also important for the accumulation of Nav channels in AIS. The findings from the study suggest that an ankyrin-G mutation could play an important role in Alzheimer’s disease (AD) pathogenesis by reducing the number of Nav channels.