The cellular environment has a profound impact on protein structure, but it is often unclear which cellular components affect the structure of a given protein. We are investigating the role of specific cellular components on protein folding and developing new chemical genetics technologies to discover previously unappreciated contributions to protein structure, particularly for misfolded proteins.
Proteins exist within a crowded and complex environment, and their frequent physical interactions alter their structure, sometimes deleteriously. Moreover, differences in the cellular environment can direct proteins toward different misfolded structures, each of which can have different activities. For example, different cell types can direct proteins toward different misfolded structures, and it is widely believed that long-term stress can alter cellular environments to promote misfolding. For some proteins that misfold, like the Parkinson's-associated protein alpha-synuclein, we know some of the cellular components that interact with the misfolding protein. Our lab is testing the effects of those components on the structure and activity of misfolded proteins. However, in general, proteins can engage in hundreds or even thousands of interactions with unknown effects on protein structure. We are therefore developing technologies that will allow us to profile protein structure in high throughput so that we can discover which cellular components are responsible for different misfolding trajectories. We believe those insights will inspire new therapeutic strategies.
Students and scientists working on these problems in our lab use techniques and approaches from structural biology, biophysics, and cell biology, including recombinant protein expression and purification, mass spectrometry, NMR, transcriptional profiling, proteomics/interactomics, library screening, next-generation sequencing, microbial culture, mammalian cell culture, live-cell imaging, flow cytometry, and bioinformatics.