Defining the Roles of Metals in Mediating Structural Changes and Protein-Protein Interactions

Metals are ubiquitous in nature. In fact, more than 30% of all proteins require a metal for proper folding or function. In this talk, I will focus on how my lab uses a range of spectroscopic characterization tools to define the role of metals on protein structure and formation of dynamic protein-protein complexes. In the first part of the talk, I will discuss the progesterone receptor membrane component 1 (PGRMC1) protein, which binds heme and is thought to interact with downstream cytochrome P450s to disrupt drug metabolism and cholesterol synthesis. Recent work has called into question the heme-triggered formation of the PGRMC1 dimer that is thought to be critical for these interactions. Using a combination of spectroscopic techniques, we have characterized the heme-PGRMC1 interaction at the secondary, quaternary, and metal-centric levels and have determined that PGRMC1 can exploit multiple paths in formation of the homodimer, albeit with different kinetics. The second half of my talk will focus on understanding the interaction of copper with huntingtin (htt) – the protein associated with Huntington’s Disease. This work is motivated by the fact that, while there is currently no cure for the disease, metal chelation therapies have emerged as promising treatment options to ameliorate symptoms. However, the metal-protein interaction is poorly understood. We combine molecular biology, spectroscopy (EPR, circular dichroism, dynamic light scattering), and in vivo Drosophila HD models to shed light on the metal-huntingtin protein interaction. Our multi-pronged approach reveals, for the first time, the impact of copper on protein aggregation across a broad spectrum of relevant length scales – from molecules to colloids to whole organs. In summation, these studies highlight the influence of metals in mediating larger protein-protein interactions of high relevance to human health.