Ion channels and ion-channel-coupled receptors are cell membrane proteins that sense physical and chemical signals and couple them with ionic flux through the cell membrane. Ion channel activity is essential for the function of almost all organs and organ systems, including the heart, the lung, the kidney, the muscular system, the nervous system, and the immune system. Consequently, the malfunction of ion channels is related to many human diseases, and ion channels have served as major drug targets.
The research in Yu lab focuses on the molecular mechanisms of the structure, function, and regulation of ion channels and receptors, as well as related disease mechanisms and drug discovery. Our long-term research goal is to understand the molecular basis of the function and regulation of these proteins and the roles they play in cell physiology and human diseases. The current major focuses in the lab is the transient receptor potential (TRP) channels and polycystin proteins. TRP channels are essential for sensory physiology and play crucial roles in many diseases. So far, TRP channels has been shown to be involved in the formation of sight, hearing, touch, smell, taste, temperature, and pain sensation. Recently, we have also been working on Otop proton channels. We use cultured mammalian cells, Xenopus oocytes and zebrafish as model systems to study structure and function of ion channels and receptors with a combined molecular biology, biochemistry, biophysics, x-ray crystallography, and electrophysiology approach.
Several our recent projects are listed below:
1) Function and regulation of the TRPP2 (polycystin-2, PKD2) channel. Mutations in transient receptor potential polycystin 2 (TRPP2) and polycystin protein PKD1 cause human autosomal dominant polycystic kidney disease (ADPKD). ADPKD is one of the most common genetic diseases in humans. TRPP2 associate with PKD1 to form a receptor-ion channel complex, which couples extracellular signal to ion flow across the cell membrane. It was very chanlenging to study function and regulation of this complex due to the lack of knowledge of its activation mechanism. Recently we generated a gain-of-function (GOF) mutant of TRPP2 channel by mutating Phe604 to proline (later we found another GOF mutant by mutating the lower gate). With this mutant, for the first time, we can reliably record robust whole cell current of TRPP2 when it is expressed in Xenopus oocytes. We have applied it into studying the molecular and cellular fucntions of TRPP2 and PKD1 and their roles in renal physiology and ADPKD (Arif Pavel et al., PNAS, 2016; Salehi-Najafabadi et al, JBC, 2017).
2) The structural and molecular basis of the TRPP/PKD complex assembly and function. TRPP/PKD protein complexes have been found to play crucial roles in many physiological signaling. However, the molecular basis of the assembly of these complexes is still poorly understood. Previously, we have demonstrated the TRPP2/PKD1 complex and the TRPP3/PKD1L3 complex have a novel stoichiometry of three TRPP subunits and one PKD subunit (Yu et al., PNAS, 2009; Zhu et al., PNAS, 2011). Furthermore, we demonstrated that PKD1L3 functions as an ion channel pore-forming subunit (Yu et al., Nat Commun, 2012). Later, with a new lower gate GOF mutation of TRPP2, we functional approved, for the first time, that the PKD1 protein is also an ion channel pore-forming subunit in the TRPP2/PKD1 complex (Wang et al., EMBO Rep, 2019). These findings define PKD protein as a new ion channel family. In a recent work, through collaboration with Dr. Yigong Shi's lab at Westlake University, we demonstrated the possible molecualr mechanism of Ca2+ activation of the TRPP3/PKD1L3 channel (Su et al., Nat Commons, 2021). We are currently looking for more detailed mechanisms of the function and regulation of the TRPP/PKD complexes. We have close collaboration with Dr. Feng Qian at the University of Maryland and Dr. Yigong Shi at Westlake University on this project.
3) Molecular mechanism of proton sensing, gating, and proton conducting of Otop proton channels. Otopetrin (Otop) proteins were recently found to function as proton channels, with Otop1 revealed to be the sour taste receptor in mammals. In this project, we investigated how human Otop1 chanenl senses the extracellular protons and conduct them through the cell membrane. We have found that two extracellular loops are playing key roles in human Otop1 channel function. We find that residue H229 in the S5-S6 loop is critical for proton sensing of Otop1. Further, our data reveal that the S11-12 loop is structurally and functionally essential for the Otop1 channel and that residue D570 in this loop regulates proton permeation into the pore formed by the C domain (Li et al., Commun Biol, 2022). We are now working on the mechanism of proton permeation through Otop channels and the role of Otop1 in sour taste.
3) Novel TRPP/PKD complexes and their roles in sensory physiology and development. Recently, several novel TRPP/PKD complexes have been shown to play crucial roles in sensory physiology and development. For example, the TRPP3/PKD1L1 complex was identified as a calcium-permeable channel essential for calcium signaling in cell cilium and the TRPP2/PKD1L1 complex was found to function as a nodal flow sensor in the early embryo and control the left-right asymmetry formation. The versatile nature of these proteins indicates that more functionally important TRPP/PKD complexes may exist. We are working on characterizing the newly identified TRPP/PKD complexes and searching for new complexes as well.
4) The lab is also working on voltage-gated calcium channels through collaboration with Dr. Nieng Yan at Princeton University and Dr. Matteo Ruggiu at St. John's University (Yao et al., Cell, 2022; Yao et al., Nat Commun, 2022).
Research in the Yu lab is funded by:
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Department of Biological Sciences l St. John's University
8000 Utopia Parkway, Queens, New York 11439