Tangled tales of proteins

Proteins are essential building blocks of life. They perform countless tasks in our cells, from providing structure to enabling chemical reactions. To function properly, proteins must fold into specific shapes. When this process fails, proteins can clump together into aggregates that are often harmful and are linked to neurodegenerative diseases such as Huntington’s disease. At the same time, controlled protein self-assembly is also responsible for remarkable natural materials, including spider silk. This thesis investigates protein aggregation from both perspectives: as a cause of disease and as a source of inspiration for advanced materials. A central part of the work focuses on Huntington’s disease, a hereditary brain disorder caused by an abnormal expansion of a repeated amino acid sequence in the huntingtin protein. This expansion promotes protein misfolding and aggregation. Using solid-state nuclear magnetic resonance (NMR) spectroscopy, this research reveals how these protein aggregates are organized at the molecular level. The aggregates consist of a rigid core surrounded by flexible regions, and a specific folded structure, known as a β-hairpin, plays a crucial role in initiating aggregation. Building on this insight, the thesis introduces a light-responsive molecular switch that allows protein aggregation to be controlled using light. This approach provides a powerful experimental tool to study aggregation and may inspire future therapeutic strategies. The interaction between huntingtin aggregates and antibodies is also explored. The results show that antibodies do not disrupt the rigid core of the aggregates but instead modify the flexible outer regions, helping to explain their potential role in diagnostics and therapy. Finally, the thesis applies similar structural principles to design spider silk–inspired materials, demonstrating how protein self-assembly can be harnessed to create strong, flexible, and sustainable biomaterials.