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Human TRPML1 channel structures in open and closed conformations

Author

Listed:
  • Philip Schmiege

    (Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University
    University of Texas Southwestern Medical Center)

  • Michael Fine

    (University of Texas Southwestern Medical Center)

  • Günter Blobel

    (Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University)

  • Xiaochun Li

    (Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University
    University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

Abstract

Transient receptor potential mucolipin 1 (TRPML1) is a Ca2+-releasing cation channel that mediates the calcium signalling and homeostasis of lysosomes. Mutations in TRPML1 lead to mucolipidosis type IV, a severe lysosomal storage disorder. Here we report two electron cryo-microscopy structures of full-length human TRPML1: a 3.72-Å apo structure at pH 7.0 in the closed state, and a 3.49-Å agonist-bound structure at pH 6.0 in an open state. Several aromatic and hydrophobic residues in pore helix 1, helices S5 and S6, and helix S6 of a neighbouring subunit, form a hydrophobic cavity to house the agonist, suggesting a distinct agonist-binding site from that found in TRPV1, a TRP channel from a different subfamily. The opening of TRPML1 is associated with distinct dilations of its lower gate together with a slight structural movement of pore helix 1. Our work reveals the regulatory mechanism of TRPML channels, facilitates better understanding of TRP channel activation, and provides insights into the molecular basis of mucolipidosis type IV pathogenesis.

Suggested Citation

  • Philip Schmiege & Michael Fine & Günter Blobel & Xiaochun Li, 2017. "Human TRPML1 channel structures in open and closed conformations," Nature, Nature, vol. 550(7676), pages 366-370, October.
    • Handle: RePEc:nat:nature:v:550:y:2017:i:7676:d:10.1038_nature24036
    DOI: 10.1038/nature24036
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    Cited by:

    1. Gamma Chi & Qiansheng Liang & Akshay Sridhar & John B. Cowgill & Kasim Sader & Mazdak Radjainia & Pu Qian & Pablo Castro-Hartmann & Shayla Venkaya & Nanki Kaur Singh & Gavin McKinley & Alejandra Ferna, 2022. "Cryo-EM structure of the human Kv3.1 channel reveals gating control by the cytoplasmic T1 domain," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Philip Schmiege & Linda Donnelly & Nadia Elghobashi-Meinhardt & Chia-Hsueh Lee & Xiaochun Li, 2024. "Structure and inhibition of the human lysosomal transporter Sialin," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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