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Related Experiment Video

Updated: Feb 21, 2026

Expression and Purification of the Human Lipid-sensitive Cation Channel TRPC3 for Structural Determination by Single-particle Cryo-electron Microscopy
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Human TRPML1 channel structures in open and closed conformations.

Philip Schmiege1,2, Michael Fine3, Günter Blobel1

  • 1Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.

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|October 12, 2017
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Summary

Researchers revealed the structure of the Transient Receptor Potential Mucolipin 1 (TRPML1) channel in closed and open states. This provides insights into calcium signaling, lysosomal function, and mucolipidosis type IV.

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Area of Science:

  • Structural biology
  • Molecular biology
  • Cell biology

Background:

  • Transient Receptor Potential Mucolipin 1 (TRPML1) is a calcium-releasing channel crucial for lysosomal calcium signaling and homeostasis.
  • Dysfunction of TRPML1 causes mucolipidosis type IV, a severe lysosomal storage disorder.

Purpose of the Study:

  • To determine the high-resolution structures of full-length human TRPML1 in both closed and open states.
  • To elucidate the molecular mechanisms underlying TRPML1 channel regulation and activation.
  • To provide insights into the structural basis of mucolipidosis type IV.

Main Methods:

  • Electron cryo-microscopy (cryo-EM) was used to obtain structures of human TRPML1.
  • Structures were determined for the apo (closed) state at pH 7.0 and the agonist-bound (open) state at pH 6.0.

Main Results:

  • Two distinct cryo-EM structures of human TRPML1 were resolved at high resolution (3.72 Å and 3.49 Å).
  • A unique hydrophobic cavity formed by specific residues in helices S5, S6, and pore helix 1 was identified as the agonist-binding site.
  • Channel opening involves dilation of the lower gate and structural shifts in pore helix 1.

Conclusions:

  • The study reveals the regulatory mechanism of TRPML channels and their activation process.
  • The findings offer a molecular understanding of mucolipidosis type IV pathogenesis.
  • This work advances the comprehension of TRP channel function and regulation.