Intrinsically disordered proteins (IDPs) and regions (IDRs) play essential roles in cellular regulation, with their functions strongly influenced by post-translational modifications. Their dysregulation often contributes to disease mechanisms in neurodegeneration and cancer. This thesis integrates nuclear magnetic resonance spectroscopy (NMR) metabolomics, NMR of proteins and de novo peptide design to address four research aims. First study explores region specific metabolic differences linked to altered arginine methylation in distinct subtypes of frontotemporal dementia with TDP-43 pathology and Alzheimer’s disease. The second part of the thesis dissects in vitro the interaction between the transcription factor FOXM1 and Wnt signalling component β-catenin, revealing a binding mechanism in which β-catenin engages multiple sites within FOXM1. Finally, solvent paramagnetic relaxation enhancement measurements were corrected by applying a theoretical model to minimize solvent-exchange driven errors, improving analysis for highly solvent-exposed disordered proteins. Together, these studies advance our understanding of metabolic alterations and their correlation with posttranslational modifications in IDP-associated neurodegenerative diseases, elucidate molecular mechanisms of pro-oncogenic IDR-involving interactions, and introduce methodological advances for studying of highly solvent-exposed IDPs with NMR.
Targeting Disordered Transcription Factors
Rakhimbekova, A. (Author). 2025
Student thesis: Doctoral thesis