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Structure of the Human TRPML2 Ion Channel Extracytosolic/Lumenal Domain.

Viet KK, Wagner A, Schwickert K, Hellwig N, Brennich M, Bader N, Schirmeister T, Morgner N, Schindelin H, Hellmich UA
Structure 27 1246-1257.e5 (2019)
Cited: 10 times
EuropePMC logo PMID: 31178222

Abstract

TRPML2 is the least structurally characterized mammalian transient receptor potential mucolipin ion channel. The TRPML family hallmark is a large extracytosolic/lumenal domain (ELD) between transmembrane helices S1 and S2. We present crystal structures of the tetrameric human TRPML2 ELD at pH 6.5 (2.0 Å) and 4.5 (2.95 Å), corresponding to the pH values in recycling endosomes and lysosomes. Isothermal titration calorimetry shows Ca2+ binding to the highly acidic central pre-pore loop which is abrogated at low pH, in line with a pH-dependent channel regulation model. Small angle X-ray scattering confirms the ELD dimensions in solution. Changes in pH or Ca2+ concentration do not affect the protein's secondary structure, but can influence ELD oligomer integrity according to native mass spectrometry. Our data thus complete the set of high-resolution views of human TRPML channel ELDs and reveal some structural responses to the conditions the TRPML2 ELD encounters as the channel traffics through the endolysosomal system.

Reviews - 6hrr mentioned but not cited (1)

  1. TRP (transient receptor potential) ion channel family: structures, biological functions and therapeutic interventions for diseases. Zhang M, Ma Y, Ye X, Zhang N, Pan L, Wang B. Signal Transduct Target Ther 8 261 (2023)

Articles - 6hrr mentioned but not cited (1)

  1. Cryo-EM structure of mouse TRPML2 in lipid nanodiscs. Song X, Li J, Tian M, Zhu H, Hu X, Zhang Y, Cao Y, Ye H, McCormick PJ, Zeng B, Fu Y, Duan J, Zhang J. J Biol Chem 298 101487 (2022)


Reviews citing this publication (6)

  1. Structural Pharmacology of TRP Channels. Zhao Y, McVeigh BM, Moiseenkova-Bell VY. J Mol Biol 433 166914 (2021)
  2. From Pinocytosis to Methuosis-Fluid Consumption as a Risk Factor for Cell Death. Ritter M, Bresgen N, Kerschbaum HH. Front Cell Dev Biol 9 651982 (2021)
  3. TRP Channels as Interior Designers: Remodeling the Endolysosomal Compartment in Natural Killer Cells. Clement D, Goodridge JP, Grimm C, Patel S, Malmberg KJ. Front Immunol 11 753 (2020)
  4. Structural biology of cation channels important for lysosomal calcium release. Gan N, Jiang Y. Cell Calcium 101 102519 (2022)
  5. LILBID-MS: using lasers to shed light on biomolecular architectures. Hellwig N, Martin J, Morgner N. Biochem Soc Trans 50 1057-1067 (2022)
  6. Mutation of TRPML1 Channel and Pathogenesis of Neurodegeneration in Haimeria. Gao J, Li H, Lv H, Cheng X. Mol Neurobiol (2023)

Articles citing this publication (2)

  1. Extent of intrinsic disorder and NMR chemical shift assignments of the distal N-termini from human TRPV1, TRPV2 and TRPV3 ion channels. Wiedemann C, Goretzki B, Merz ZN, Tebbe F, Schmitt P, Hellmich UA. Biomol NMR Assign 16 289-296 (2022)
  2. A Structural Overview of TRPML1 and the TRPML Family. Fine M, Li X. Handb Exp Pharmacol 278 181-198 (2023)


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