Biophysical factors governing the structure, function, and dynamics of the NF-κB essential modulator protein (NEMO)

Abstract

The NF-κB essential modulator (NEMO) is an important human protein, in charge of ensuring the activation the NF-κB signalling pathway in response to canonical stimuli. Very little consensus exists about the structure, dynamics, and the role of the protein. Here we offer evidence to support the dynamic nature of NEMO, with binding to ligands inducing a ligand-dependent conformational change in the protein. We propose the use of an optical phenomenon known as Red edge excitation shift (REES) as a new tool to study and quantify protein dynamics. We also emphasise the importance of taking into consideration the effect of the intracellular environment on modulating the structure and dynamics of NEMO. Furthermore, we shed light onto the cytoplasmic role of NEMO in mediating an important enzyme:susbstrate interaction as part of NF-κB activation. These findings underline the dynamic nature of NEMO and its sensitivity to the environment and may also explain the diversity of data published of NEMO so far. Moreover, we also offer evidence to support the importance of NEMO presence for the interaction between IKKβ:IκBα during NF-κB canonical activation. These are potentially crucial aspects to be considered when developing therapeutic targets that aim to modulate the abnormal NF-κB response in many human medical conditions.

Date of Award	19 Jun 2019
Original language	English
Awarding Institution	University of Bath
Sponsors	Engineering and Physical Sciences Research Council
Supervisor	David Leak (Supervisor) & Christopher Pudney (Supervisor)