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Structural basis for PtdInsP2-mediated human TRPML1 regulation.

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Fine M, Schmiege P, Li X
OpenAccess logo Nat Commun 9 4192 (2018)
Related entries: 6e7p, 6e7y

Cited: 41 times
EuropePMC logo PMID: 30305615

Abstract

Transient receptor potential mucolipin 1 (TRPML1), a lysosomal channel, maintains the low pH and calcium levels for lysosomal function. Several small molecules modulate TRPML1 activity. ML-SA1, a synthetic agonist, binds to the pore region and phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), a natural lipid, stimulates channel activity to a lesser extent than ML-SA1; moreover, PtdIns(4,5)P2, another natural lipid, prevents TRPML1-mediated calcium release. Notably, PtdIns(3,5)P2 and ML-SA1 cooperate further increasing calcium efflux. Here we report the structures of human TRPML1 at pH 5.0 with PtdIns(3,5)P2, PtdIns(4,5)P2, or ML-SA1 and PtdIns(3,5)P2, revealing a unique lipid-binding site. PtdIns(3,5)P2 and PtdIns(4,5)P2 bind to the extended helices of S1, S2, and S3. The phosphate group of PtdIns(3,5)P2 induces Y355 to form a π-cation interaction with R403, moving the S4-S5 linker, thus allosterically activating the channel. Our structures and electrophysiological characterizations reveal an allosteric site and provide molecular insight into how lipids regulate TRP channels.

Reviews - 6e7z mentioned but not cited (3)

  1. Advances in TRP channel drug discovery: from target validation to clinical studies. Koivisto AP, Belvisi MG, Gaudet R, Szallasi A. Nat Rev Drug Discov 21 41-59 (2022)
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  6. Transmembrane 163 (TMEM163) Protein: A New Member of the Zinc Efflux Transporter Family. Styrpejko DJ, Cuajungco MP. Biomedicines 9 220 (2021)
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  1. Interfacial Binding Sites for Cholesterol on TRP Ion Channels. Lee AG. Biophys J 117 2020-2033 (2019)
  2. Structural mechanisms of transient receptor potential ion channels. Cao E. J Gen Physiol 152 (2020)
  3. Atomic insights into ML-SI3 mediated human TRPML1 inhibition. Schmiege P, Fine M, Li X. Structure 29 1295-1302.e3 (2021)
  4. Cryo-EM structure of the lysosomal chloride-proton exchanger CLC-7 in complex with OSTM1. Schrecker M, Korobenko J, Hite RK. Elife 9 (2020)
  5. Lipid Interactions of a Ciliary Membrane TRP Channel: Simulation and Structural Studies of Polycystin-2. Wang Q, Corey RA, Hedger G, Aryal P, Grieben M, Nasrallah C, Baronina A, Pike ACW, Shi J, Carpenter EP, Sansom MSP. Structure 28 169-184.e5 (2020)
  6. Mitochondria-lysosome contacts regulate mitochondrial Ca2+ dynamics via lysosomal TRPML1. Peng W, Wong YC, Krainc D. Proc Natl Acad Sci U S A 117 19266-19275 (2020)
  7. Expanding the Toolbox: Novel Modulators of Endolysosomal Cation Channels. Rautenberg S, Keller M, Leser C, Chen CC, Bracher F, Grimm C. Handb Exp Pharmacol 278 249-276 (2023)
  8. Global alignment and assessment of TRP channel transmembrane domain structures to explore functional mechanisms. Huffer KE, Aleksandrova AA, Jara-Oseguera A, Forrest LR, Swartz KJ. Elife 9 (2020)
  9. Methods to study phosphoinositide regulation of ion channels. Yudin Y, Liu L, Nagwekar J, Rohacs T. Methods Enzymol 652 49-79 (2021)
  10. A Structural Overview of TRPML1 and the TRPML Family. Fine M, Li X. Handb Exp Pharmacol 278 181-198 (2023)
  11. A novel BRET-based assay to investigate binding and residence time of unmodified ligands to the human lysosomal ion channel TRPML1 in intact cells. Cunha MR, Catta-Preta CMC, Takarada JE, Moreira GA, Massirer KB, Couñago RM. J Biol Chem 299 104807 (2023)
  12. Activated Endolysosomal Cation Channel TRPML1 Facilitates Maturation of α-Synuclein-Containing Autophagosomes. Pollmanns MR, Beer J, Rosignol I, Rodriguez-Muela N, Falkenburger BH, Dinter E. Front Cell Neurosci 16 861202 (2022)
  13. 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)
  14. Interaction between TRPML1 and p62 in Regulating Autophagosome-Lysosome Fusion and Impeding Neuroaxonal Dystrophy in Alzheimer's Disease. Zhang L, Fang Y, Cheng X, Lian Y, Xu H. Oxid Med Cell Longev 2022 8096009 (2022)
  15. Lipid kinases VPS34 and PIKfyve coordinate a phosphoinositide cascade to regulate retriever-mediated recycling on endosomes. Giridharan SSP, Luo G, Rivero-Rios P, Steinfeld N, Tronchere H, Singla A, Burstein E, Billadeau DD, Sutton MA, Weisman LS. Elife 11 e69709 (2022)
  16. Lipid⁻Protein Interactions in Niemann⁻Pick Type C Disease: Insights from Molecular Modeling. Wheeler S, Schmid R, Sillence DJ. Int J Mol Sci 20 (2019)
  17. Mapping of CaM, S100A1 and PIP2-Binding Epitopes in the Intracellular N- and C-Termini of TRPM4. Bousova K, Barvik I, Herman P, Hofbauerová K, Monincova L, Majer P, Zouharova M, Vetyskova V, Postulkova K, Vondrasek J. Int J Mol Sci 21 (2020)
  18. Molecular architecture of the Gαi-bound TRPC5 ion channel. Won J, Kim J, Jeong H, Kim J, Feng S, Jeong B, Kwak M, Ko J, Im W, So I, Lee HH. Nat Commun 14 2550 (2023)
  19. Structural mechanism of allosteric activation of TRPML1 by PI(3,5)P2 and rapamycin. Gan N, Han Y, Zeng W, Wang Y, Xue J, Jiang Y. Proc Natl Acad Sci U S A 119 e2120404119 (2022)
  20. Structure of Heteropentameric GABAA Receptors and Receptor-Anchoring Properties of Gephyrin. Kasaragod VB, Schindelin H. Front Mol Neurosci 12 191 (2019)
  21. TRP channels in health and disease at a glance. Yue L, Xu H. J Cell Sci 134 jcs258372 (2021)
  22. The chloride antiporter CLCN7 is a modifier of lysosome dysfunction in FIG4 and VAC14 mutants. Cao X, Lenk GM, Mikusevic V, Mindell JA, Meisler MH. PLoS Genet 19 e1010800 (2023)
  23. The intracellular Ca2+ channel TRPML3 is a PI3P effector that regulates autophagosome biogenesis. Kim SW, Kim MK, Hong S, Choi A, Choi JH, Muallem S, So I, Yang D, Kim HJ. Proc Natl Acad Sci U S A 119 e2200085119 (2022)
  24. The synthetic TRPML1 agonist ML-SA1 rescues Alzheimer-related alterations of the endosomal-autophagic-lysosomal system. Somogyi A, Kirkham ED, Lloyd-Evans E, Winston J, Allen ND, Mackrill JJ, Anderson KE, Hawkins PT, Gardiner SE, Waller-Evans H, Sims R, Boland B, O'Neill C. J Cell Sci 136 jcs259875 (2023)
  25. Tonic inhibition of the chloride/proton antiporter ClC-7 by PI(3,5)P2 is crucial for lysosomal pH maintenance. Leray X, Hilton JK, Nwangwu K, Becerril A, Mikusevic V, Fitzgerald G, Amin A, Weston MR, Mindell JA. Elife 11 e74136 (2022)
  26. Transient receptor potential ion-channel subfamily V member 4: a potential target for cancer treatment. Yu S, Huang S, Ding Y, Wang W, Wang A, Lu Y. Cell Death Dis 10 497 (2019)


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