Investigation of RE1-Silencing Transcription factor (REST) as transcriptional regulator in neurodegenerative diseases by Molecular Modeling
Project no. 24211 · Status: Kapanmış · 2022
Summary
<p>The RE1-silencing transcription factor (REST) functions as a transcriptional repressor, silencing target genes through epigenetic remodeling processes. REST additionally functions as the primary transcriptional controller for neuron-specific genes in mature neurons during vital phases of postnatal brain development. An imbalance in gene expression, which is crucial in the progression of various neurodegenerative disorders, can result from the impairment of REST’s regulatory and repressive capabilities.</p><p>This thesis aimed to investigate the structural and dynamic characteristics of various REST protein isoforms, which are intrinsically disordered region (IDR)-rich transcriptional repressors, in light of phosphorylation effects. In pursuit of this goal, specific phosphorylated (P) and non-phosphorylated (NP) configurations of the REST protein's binding and repression domains were modeled with AlphaFold2 software. Over a 100 ns period, molecular dynamics (MD) simulations were carried out using the Amber20 software and the CHARMM36m force field. A comprehensive analysis of the structural flexibility and conformational shifts was performed on the collected simulation data. This marks the initial occasion in documented studies where a comprehensive evaluation of all REST protein isoform structures was conducted, along with an examination of phosphorylation's impact.</p><p>Our study shows that the phosphorylation of the REST protein, through its interplay with intrinsically disordered regions, plays a critical part in shaping the structural movements among diverse isoform structures and zinc finger motifs. Future studies that meticulously examine the interaction potentials of the resulting structures via molecular modeling methods could be instrumental in advancing specific diagnostic and treatment strategies for diseases affecting the nervous system.</p>