Pathogenic Proteins Through the Lens of NMR Spectroscopy: Structural and Functional Insights into Disease.

Proteins are essential for cell functions, and their dysfunction—including misfolding, aggregation, abnormal interactions, and specific post-translational modifications—is closely linked to many diseases, such as neurodegenerative, infectious, and cancerous conditions. Therefore, accurately identifying and thoroughly characterizing disease-causing proteins is crucial for understanding disease mechanisms and developing effective treatments. However, studying disease-related proteins in complex biological systems remains challenging due to factors such as their conformational diversity, often low levels in the body, and the complexity of the cellular environment. Nuclear Magnetic Resonance (NMR) spectroscopy, with its exceptional ability to examine protein structure, dynamics, and interactions at the atomic level in solution, in cells, and in solid states, has become an essential tool for understanding these diseases. This review will examine recent advancements in NMR methods, with a specific focus on how these improvements have enhanced their capacity to investigate protein-related pathologies. The primary focus will be on NMR’s unique capacity to identify abnormal protein shapes and interactions in disease states, uncover the molecular mechanisms behind pathogenicity, and ultimately guide the development of targeted therapies.