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Structural Analysis of TRPV2 by Cryo-Electron Microscopy Reveals Regulatory Diversity Among the ThermoTRPV Channels

Huynh, Kevin Weijian

Abstract Details

2016, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
Transient receptor potential (TRP) proteins are a large family of polymodal non-selective cation channels. The TRP vanilloid (TRPV) subfamily consists of six homologous members with diverse functions: TRPV1-4 (thermoTRPVs) are non-selective cation channels proposed to play a role in nociception, while TRPV5 and TRPV6 are involved in epithelial Ca2+ homeostasis. TRPV2 channel is ubiquitously expressed in many cell types and is involved in a variety of physiological functions including neuronal development, cardiac maintenance, cancer and chronic pain. However, the molecular role of TRPV2 in these various physiological functions has remained undetermined. Therefore, studying the structure of TRPV2 channel in different conformations or states will provide insights into their diverse regulatory mechanisms. Here we present the cryo-electron microscopy (cryo-EM) structure of functional, full-length, ligand-free TRPV2 resolved from 13.6 Å to 4.5 Å. The moderate resolution structure reveals the general “hanging gondola” architecture conserved throughout the thermoTRPVs. Additionally, the transmembrane domain with the detergent belt and the cytoplasmic domain are clearly identified from the structure. The near-atomic resolution structure shows a similar dual-gate pore shown in the TRPV1 structures, which is about 50% sequence identical to TRPV2. However, the ligand-free, full-length TRPV2 structure has a wider pore architecture compared to the ligand-free, “minimum subunit” TRPV1, suggesting that either the two channels have different intrinsic pore conformations or that the pore turret, which was truncated in TRPV1, may be essential for gating. Overall, this dissertation will examine the regulatory diversity among the thermoTRPV channels and provide insight into the potential role of the pore turret domain in TRPV2 channel gating.
Vera Moiseenkova-Bell (Advisor)
Phoebe Stewart (Committee Chair)
Ruth Keri (Committee Member)
Sudha Chakrapani (Committee Chair)
Jenny Hinshaw (Committee Chair)
179 p.

Recommended Citations

Citations

  • Huynh, K. W. (2016). Structural Analysis of TRPV2 by Cryo-Electron Microscopy Reveals Regulatory Diversity Among the ThermoTRPV Channels [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1467996438

    APA Style (7th edition)

  • Huynh, Kevin. Structural Analysis of TRPV2 by Cryo-Electron Microscopy Reveals Regulatory Diversity Among the ThermoTRPV Channels. 2016. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1467996438.

    MLA Style (8th edition)

  • Huynh, Kevin. "Structural Analysis of TRPV2 by Cryo-Electron Microscopy Reveals Regulatory Diversity Among the ThermoTRPV Channels." Doctoral dissertation, Case Western Reserve University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1467996438

    Chicago Manual of Style (17th edition)