Hot topic: Cryo-EM structures of Mucolipin TRP Channels in the Lysosome: Five Together at Once

The mucolipin subfamily of Transient Receptor Potential (TRP) channels, which consist of TRPML1, TRPML2, and TRPML3 (a.k.a. MCOLN1- 3), are Ca²⁺-permeable cation channels localized in intracellular endosomes and lysosomes. In response to cellular stimulation, TRPMLs mediate Ca²⁺ release from the lysosome lumen, triggering Ca²⁺-dependent lysosomal membrane trafficking events involved in a variety of basic cell biological processes, including lysosomal exocytosis, autophagy, and membrane repair [1]. In humans, loss-of-function mutations of TRPML1 cause type IV Mucolipidosis (ML-IV), a lysosome storage neurodegenerative disease (LSD). In mice, gain-of-function mutations of TRPML3 cause pigmentation and hearing defects [1]. Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P₂), an endolysosome-specific phosphoinositide, may serve as an endogenous agonist of TRPMLs [2]. In addition, mucolipin-specific synthetic agonists (ML-SAs) have been identified and shown to regulate various TRPML-dependent lysosome functions by mimicking endogenous agonists [3]. Now, five independent studies, led by Youxing Jiang, Xiaochun Li, Soek-yong Lee, Maojun Yang, and Jian Yang, respectively, report a total of three TRPML1 and two TRPML3 Cryo-EM structures, all at atomic resolution, and in both closed and agonist-bound open conformations [4-8]. The general features of these channels are consistent across all five studies. Consistent with previous work [2], positively-charged amino acid residues in the cytoplasmic N–terminus are found to be responsible for channel activation by PI(3,5)P₂ [7, 8]. In contrast, the synthetic agonist ML-SA1 binds to a separate site at an intriguing location. TRPML1 and TRPML3 are six-transmembrane (6TM) channel proteins with an overall topology similar to many other tetrameric cation channels, including K_V channels. ML-SA1 binds to residues in the S5 and S6 [4, 6], domains that are known to form the “activation gate”. These five studies have provided a structural foundation for studying TRPML channel regulation, pharmacology, and lysosome chemical biology, which in turn may help develop new therapeutic strategies for a spectrum of lysosome-related diseases, including ML-IV, other LSDs, and common neurodegenerative diseases.

Comments by Haoxing Xu, NC-IUPHAR subcommittee Chair of the Transient Receptor Potential Channels and Professor, the University of Michigan

References

1. Xu, H. and D. Ren, Lysosomal physiology. Annu Rev Physiol, 2015. 77: p. 57-80. [PMID:25668017]

2. Dong, X.P., et al., PI(3,5)P(2) Controls Membrane Traffic by Direct Activation of Mucolipin Ca Release Channels in the Endolysosome. Nat Commun, 2010. 1(4). [PMID:20802798]

3. Shen, D., et al., Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release. Nat Commun, 2012. 3: p. 731. [PMID:22415822]

4. Zhou, X., et al., Cryo-EM structures of the human endolysosomal TRPML3 channel in three distinct states. Nat Struct Mol Biol, 2017. [PMID:29106414]

5. Zhang, S., et al., Cryo-EM structures of the mammalian endo-lysosomal TRPML1 channel elucidate the combined regulation mechanism. Protein Cell, 2017. 8(11): p. 834-847. [PMID:28936784]

6. Schmiege, P., et al., Human TRPML1 channel structures in open and closed conformations. Nature, 2017. 550(7676): p. 366-370. [PMID:29019983]

7. Hirschi, M., et al., Cryo-electron microscopy structure of the lysosomal calcium-permeable channel TRPML3. Nature, 2017. 550(7676): p. 411-414. [PMID:29019979]

8. Chen, Q., et al., Structure of mammalian endolysosomal TRPML1 channel in nanodiscs. Nature, 2017. 550(7676): p. 415-418. [PMID:29019981]