Translating structure-function to therapeutics:
1. How are ions and lipids transported through cell membranes?
A. Calcium-activated chloride channels
- The structural basis of the calcium-dependent activation of TMEM16 proteins (Tien, et al, eLife, 2014)
- The third calcium binding site that allosterically regulates TMEM16A activation (Le and Yang, Cell Reports, 2020)
- Elucidated the molecular basis of TMEM16A channel desensitization and the modular design of TMEM16 proteins (Le, et al, Nat. Commun., 2019)
B. Calcium-activated lipid scramblases
- Discovered an activation gate that controls TMEM16 lipid and ion transport (Le, et al, Nat. Commun., 2019)
- Subdued is a new calcium-activated lipid scramblase with non-selective channel functions in Drosophila (Le, et al, JBC, 2019)
- Uncovered the mechanism of pH regulation of TMEM16 scramblases and channels. (Liang and Yang, J. Gen. Physiol. 2020). See Commentary here.
2. What are the biological functions of ion and lipid transport?
A. Calcium-activated chloride channels
- TMEM16B as an overlooked calcium-activated chloride channel mediates cerebellar motor learning (Zhang, et al, Neuron, 2017)
B. Calcium-activated lipid scramblases
- TMEM16F, a calcium-activated ion channel and lipid scramblase, plays a critical role in blood coagulation (Yang, et al, Cell, 2012)
- Deciphering and disrupting PIEZO1-TMEM16F interplay in Hereditary Xerocytosis (HX), a rare red blood disorder (Liang, et al, Blood, 2024). See Commentary here.
- TMEM16F-mediated phosphatidylserine exposure is critical for placental trophoblast fusion and placental development. (Zhang et al. Sci. Adv., 2020)
- Discovered placental TRPV4 that regulates TMEM16F activation and trophoblast fusion. (Yang et al, eLife, 2022)
3. What if ion and lipid transport goes awry?
A. BK channelopathy
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- Seventeen years after discovering the D434G mutation in the BK channel linked to absence seizures and dyskinesia, we studied it using a knockin mouse model. This model mirrored clinical symptoms, revealed neuronal bases, and suggested a therapeutic approach for the channelopathy. (Dong, et al, PNAS, 2022).
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- Collaborating with the Mikati lab and the Cui lab, we identified and characterized a novel BK gain-of-function mutation that causes dystonia (Zhang, et al, Mov. Disord. , 2020)
4. How to control ion and lipid transport to treat diseases?
5. Method development
- Developed an optimized fluoresence imaging assay to quantify lipid scrambling.
- Developed a simple and robust fluorescent labeling method to quantify cell-cell fusion. (Zhang and Yang, Placenta, 2019)