Decoding protein degradation with structural biology and machine learning
Adam Middleton
Senior Research Fellow, Department of Biochemistry
University of Otago
Thursday, May 29, 2025
9:30 a.m.
In-person: C2-361
Abstract: The post-translational modification of proteins with ubiquitin has a central role in all eukaryotic cells. As a result, disruption of ubiquitin transfer is associated with many illnesses including cancer, diabetes, and neurological disease. Ubiquitin modification regulates the fate of substrate proteins, particularly directing substrates for destruction by the proteasome. I use a combination of structural and computational methods to understand how ubiquitin signals are generated, and develop new tools to control ubiquitin signaling.
Here I will discuss how we have used phage display to discover protein-based inhibitors of the ubiquitin cascade. Our targets are enzymes that are central to ubiquitin transfer where they play an essential role in adding a degradative signal to substrate proteins, such as p53, as well as being involved in the development of neurodegenerative disease. Our inhibitors are potent and specific, and structural and biochemical analyses allowed us to establish how they can inhibit activity. Overall this project reveals a potential hot-spot for future therapeutic design and a framework for development of useful research tools. In the second part, I will discuss an ongoing project investigating a protein that may act as a switch that controls degradation of mitochondria. For this, I am using a combination of Alphafold, structural biology, and biochemical assays to determine how this protein helps maintain healthy mitochondria. Finally, I will highlight how AI-based structure prediction and design tools will enable new frontiers of protein degradation research.