Insights into conformational heterogeneity of an RRM: implications for fibril formation

Abstract

Proteins are inherently dynamic entities, existing not as a single static structure but as an ensemble of different conformations. These conformations are separated by small free energy differences and reflect the important mechanistic aspects of their function, allowing proteins to adapt to various physiological conditions. Some proteins undergo rapid conformational shifts, while others might change more slowly or in more distinct ways. Understanding these dynamic processes is critical for gaining a deeper insight into macromolecular function and has significant implications for therapeutic drug design.

FUS-RRM (Fused in Sarcoma - RNA Recognition Motif) domain is well-folded in its native state, and undergoes aggregation when agitated. A correlation between the conformational heterogeneity of FUS-RRM and its aggregation behavior has not been explored till date. FUS-RRM aggregation has been linked to neurodegenerative diseases, particularly Amyotrophic Lateral Sclerosis (ALS). When FUS proteins aggregate upon stress or mutation, they form cytoplasmic inclusions that disrupt cellular function and contribute to disease pathology. Understanding the conformational dynamics behind FUS-RRM aggregation could provide insights into the molecular mechanisms that drive ALS pathology. This research aims to explore the structural and dynamic aspects of FUS-RRM aggregation by external perturbations such as pH and ATP, by employing advanced Nuclear Magnetic Resonance (NMR) spectroscopy and other biophysical tools. NMR offers high-resolution insights into protein dynamics, allowing access to structural changes over a range of timescales. By capturing these dynamic processes, this research illuminates the mechanisms that drive FUS-RRM aggregation and how these processes might be influenced or inhibited.