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5 Publications

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    11/11/18 | Cryo-EM structure of the receptor-activated TRPC5 ion channel at 2.9 angstrom resolution.
    Jingjing Duan , Jian Li , Gui-Lan Chen , Bo Zeng , Kechen Xie , Xiaogang Peng , Wei Zhou , Jianing Zhong , Yixing Zhang , Jie Xu , Changhu Xue , Lan Zhu , Wei Liu , Xiao-Li Tian , Jianbin Wang , David E. Clapham , Zongli Li , Jin Zhang

    The transient receptor potential canonical subfamily member 5 (TRPC5) is a non-selective calcium-permeant cation channel. As a depolarizing channel, its function is studied in the central nervous system and kidney. TRPC5 forms heteromultimers with TRPC1, but also forms homomultimers. It can be activated by reducing agents through reduction of the extracellular disulfide bond. Here we present the 2.9 Å resolution electron cryo-microscopy (cryo-EM) structure of TRPC5. The structure of TRPC5 in its apo state is partially open, which may be related to the weak activation of TRPC5 in response to extracellular pH. We also report the conserved negatively charged residues of the cation binding site located in the hydrophilic pocket between S2 and S3. Comparison of the TRPC5 structure to previously determined structures of other TRPC and TRP channels reveals differences in the extracellular pore domain and in the length of the S3 helix. Together, these results shed light on the structural features that contribute to the specific activation mechanism of the receptor-activated TRPC5.

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    08/14/18 | Structure of the mammalian TRPM7, a magnesium channel required during embryonic development.
    Duan J, Li Z, Li J, Hulse RE, Santa-Cruz A, Valinsky WC, Abiria SA, Krapivinsky G, Zhang J, Clapham DE
    Proceedings of the National Academy of Sciences of the United States of America. 2018 Aug 14;115(35):E8201-10. doi: 10.1073/pnas.1810719115

    The transient receptor potential ion channel subfamily M, member 7 (TRPM7), is a ubiquitously expressed protein that is required for mouse embryonic development. TRPM7 contains both an ion channel and an α-kinase. The channel domain comprises a nonselective cation channel with notable permeability to Mg and Zn Here, we report the closed state structures of the mouse TRPM7 channel domain in three different ionic conditions to overall resolutions of 3.3, 3.7, and 4.1 Å. The structures reveal key residues for an ion binding site in the selectivity filter, with proposed partially hydrated Mg ions occupying the center of the conduction pore. In high [Mg], a prominent external disulfide bond is found in the pore helix, which is essential for ion channel function. Our results provide a structural framework for understanding the TRPM1/3/6/7 subfamily and extend the knowledge base upon which to study the diversity and evolution of TRP channels.

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    08/06/18 | Structure of the mouse TRPC4 ion channel.
    Duan J, Li J, Zeng B, Chen G, Peng X, Zhang Y, Wang J, Clapham DE, Li Z, Zhang J
    Nature Communications. 2018 Aug 06;9(1):3102. doi: 10.1038/s41467-018-05247-9

    Members of the transient receptor potential (TRP) ion channels conduct cations into cells. They mediate functions ranging from neuronally mediated hot and cold sensation to intracellular organellar and primary ciliary signaling. Here we report a cryo-electron microscopy (cryo-EM) structure of TRPC4 in its unliganded (apo) state to an overall resolution of 3.3 Å. The structure reveals a unique architecture with a long pore loop stabilized by a disulfide bond. Beyond the shared tetrameric six-transmembrane fold, the TRPC4 structure deviates from other TRP channels with a unique cytosolic domain. This unique cytosolic N-terminal domain forms extensive aromatic contacts with the TRP and the C-terminal domains. The comparison of our structure with other known TRP structures provides molecular insights into TRPC4 ion selectivity and extends our knowledge of the diversity and evolution of the TRP channels.

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    07/13/18 | Cryo-EM structure of the polycystin 2-l1 ion channel.
    Hulse RE, Li Z, Huang RK, Zhang J, Clapham DE
    eLife. 2018 Jul 13;7:. doi: 10.7554/eLife.36931

    We report the near atomic resolution (3.3 Å) of the human polycystic kidney disease 2-like 1 (polycystin 2-l1) ion channel. Encoded by PKD2L1, polycystin 2-l1 is a calcium and monovalent cation-permeant ion channel in primary cilia and plasma membranes. The related primary cilium-specific polycystin-2 protein, encoded by PKD2, shares a high degree of sequence similarity, yet has distinct permeability characteristics. Here we show that these differences are reflected in the architecture of polycystin 2-l1.

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    02/20/18 | Structure of full-length human TRPM4.
    Duan J, Li Z, Li J, Santa-Cruz A, Sanchez-Martinez S, Zhang J, Clapham DE
    Proceedings of the National Academy of Sciences of the United States of America. 2018 Feb 20;115(10):2377-82. doi: 10.1073/pnas.1722038115

    Transient receptor potential melastatin subfamily member 4 (TRPM4) is a widely distributed, calcium-activated, monovalent-selective cation channel. Mutations in human TRPM4 (hTRPM4) result in progressive familial heart block. Here, we report the electron cryomicroscopy structure of hTRPM4 in a closed, Na-bound, apo state at pH 7.5 to an overall resolution of 3.7 Å. Five partially hydrated sodium ions are proposed to occupy the center of the conduction pore and the entrance to the coiled-coil domain. We identify an upper gate in the selectivity filter and a lower gate at the entrance to the cytoplasmic coiled-coil domain. Intramolecular interactions exist between the TRP domain and the S4-S5 linker, N-terminal domain, and N and C termini. Finally, we identify aromatic interactions via π-π bonds and cation-π bonds, glycosylation at an N-linked extracellular site, a pore-loop disulfide bond, and 24 lipid binding sites. We compare and contrast this structure with other TRP channels and discuss potential mechanisms of regulation and gating of human full-length TRPM4.

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