Chemistry and Materials Science Seminar: Homo- and heterotypic protein-protein interactions implicated in neurodegenerative disease
Chemistry and Materials Science Seminar
Homo- and heterotypic protein-protein interactions implicated in neurodegenerative disease
Dr. Kaylee Mathews ’16
Post-Doctoral Research Associate
Brown University
RIT Biochemistry BS, 2016
Register Here for Zoom Link
This seminar may be attended in person in 2305 Gosnell Hall or online via Zoom.
Dr. Mathews will present a biophysical and biochemical characterization of the Protein-protein interactions (PPIs) of several proteins implicated in neurodegenerative disease using NMR spectroscopy, as well as using NMR to further investigate PPIs related to understand neurodegenerative disease mechanisms.
Abstract:
RNA-binding proteins (RBPs) interact with a network of other proteins to form ribonucleoprotein (RNP) complexes, which are critical players throughout the lifecycle of RNA. Dysfunction of RBPs has been implicated in many human diseases like cancers and neurodegenerative diseases. For example, trans-activating response protein of 43 kDa (TDP-43) and heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2) are RBPs that are implicated in amyotrophic lateral sclerosis (ALS) and other similar diseases. Furthermore, mutations associated with disease have been identified in their low-complexity domains (LCs). Another RBP associated with neurodegeneration is the survival motor neuron protein (SMN), and low levels cause spinal muscular atrophy (SMA). Each of these proteins participates in critical protein-protein interactions (PPIs) that have yet to be studied structurally. Here, we present a biophysical and biochemical characterization of the PPIs of several proteins implicated in neurodegenerative disease. First, we used nuclear magnetic resonance (NMR) spectroscopy to study cyclophilin A (CypA) binding to TDP-43 C-terminal domain (CTD) and hnRNPA2 LC and found that CypA directly but weakly binds TDP-43 CTD and hnRNPA2 LC at their GP motifs, disease mutations disrupt binding, and CypA is recruited to their in vitro liquid-liquid phase-separated droplets. CypA binding is weak, but disruption of binding by mutations may cause disease. Second, we again used NMR spectroscopy to show that the proline-rich region of SMN interacts with profilin-1 (PFN1) at each of its polyproline motifs and disease mutations either enhance or disrupt binding. Disruption of binding by mutations may cause disease, highlighting the importance of these findings. Finally, we showed that SMN CTD assembles into oligomers much larger than previously reported via thermostable helix-helix contacts. SMN oligomerization is critical for proper SMN function and thus, understanding its mechanisms are critical to understanding SMA. Due to the prevalence of RBPs implicated in neurodegenerative disease, understanding their functional and dysfunctional protein-protein interactions is critical to fully understanding neurodegenerative disease mechanisms.
Speaker Bio:
Kaylee Mathews is currently a postdoctoral research associate at Brown University in the laboratory of Dr. Nicolas Fawzi where she earned her Ph.D. in September 2021 in Molecular Biology, Cell Biology, and Biochemistry. Her work focuses primarily on using nuclear magnetic resonance (NMR) spectroscopy and biochemical techniques to answer biological questions regarding the structure, interactions, and liquid-liquid phase separation behavior of proteins implicated in neurodegenerative diseases. During her graduate career, Kaylee was very active in her graduate program where she served on committees including those responsible for first-year mentoring, organization of structural biology seminars, and diversity, equity, and inclusivity initiatives. As an undergraduate student she attended Rochester Institute of Technology and earned her B.S. in Biochemistry in 2016. At RIT, she worked with Drs. Lea Vacca Michel, George Thurston, and Jeffrey Mills where she studied the self-interaction of an eye lens protein using NMR spectroscopy.
Intended Audience:
Undergraduates, graduates, experts. Those with interest in the topic.
To request an interpreter, please visit myaccess.rit.edu
Event Snapshot
When and Where
Who
Open to the Public
Interpreter Requested?
No