2024 Theses Doctoral
Structural studies of TRPML2 channels
Ion channels are fundamental and essential molecular machineries located in the membranes of diverse organelles, crucial for maintaining normal cellular function in response to various stimuli. The TRP channel family, discovered in the late 1980s, has been extensively studied for its structures and functions. TRP channels are involved in a broad spectrum of sensory processes such as temperature sensation, touch, pain, and osmolarity regulation. Given their role in sensing diverse stimuli, TRP channels play numerous physiological and pathological roles and have emerged as valuable therapeutic targets for various diseases. As a subfamily of the TRP channel superfamily, TRPML channels also fulfill various physiological functions.
Among the TRPML channel subfamilies, TRPML1 and TRPML3 have been identified due to their association with human and mouse disease phenotypes, highlighting their crucial roles in maintaining cellular function and contributing to disease progression when dysfunctional. TRPML1 is extensively studied, likely due to its direct link to human diseases. In contrast, TRPML2 has not been extensively studied because it is not implicated in any disease phenotype. While they are expected to share specific biophysical properties and functions, recent research has increasingly focused on uncovering the unique and essential physiological roles of TRPML2. Studies have revealed its involvement as an osmo/mechanosensitive channel in the immune system and its structure in its apo state. However, further research is needed to fully understand the molecular mechanisms and broader physiological functions of TRPML2.
In my thesis, I employ single-particle cryogenic electron microscopy (cryo-EM) to elucidate the structures of human and mouse TRPML2 in the presence of natural and synthetic agonists. These structures highlight distinctive structural characteristics of TRPML2 compared to other TRPML channels and suggest a cooperative and non-canonical activation mechanism involving multiple agonists under experimental conditions. Additionally, electrophysiology experiments were conducted to explore the relationship between the structure and function of human TRPML2.
Overall, my thesis work contributes to uncovering unique structural elements and presents the first open-state structure of TRPML2. Furthermore, it offers insights into how TRPML2 interacts with ligands and is activated through a novel activation mechanism.
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More About This Work
- Academic Units
- Biological Sciences
- Thesis Advisors
- Yang, Jian
- Degree
- Ph.D., Columbia University
- Published Here
- September 11, 2024