| Structural highlights
Function
[MCLN2_HUMAN] Nonselective cation channel probably playing a role in the regulation of membrane trafficking events. Acts as Ca(2+)-permeable cation channel with inwardly rectifying activity (PubMed:19940139, PubMed:19885840). May activate ARF6 and be involved in the trafficking of GPI-anchored cargo proteins to the cell surface via the ARF6-regulated recycling pathway (PubMed:17662026). May play a role in immune processes. In adaptive immunity, TRPML2 and TRPML1 may play redundant roles in the function of the specialized lysosomes of B cells (By similarity). In the innate immune response, may play a role in the regulation of chemokine secretion and macrophage migration (By similarity). Through a possible and probably tissue-specific heteromerization with MCOLN1 may be at least in part involved in many lysosome-dependent cellular events (PubMed:19885840).[UniProtKB:Q8K595][1] [2] [3]
Publication Abstract from PubMed
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 A) and 4.5 (2.95 A), corresponding to the pH values in recycling endosomes and lysosomes. Isothermal titration calorimetry shows Ca(2+) 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 Ca(2+) 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.
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. 2019 May 14. pii: S0969-2126(19)30161-3. doi:, 10.1016/j.str.2019.04.016. PMID:31178222[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Karacsonyi C, Miguel AS, Puertollano R. Mucolipin-2 localizes to the Arf6-associated pathway and regulates recycling of GPI-APs. Traffic. 2007 Oct;8(10):1404-14. doi: 10.1111/j.1600-0854.2007.00619.x. Epub 2007, Jul 29. PMID:17662026 doi:http://dx.doi.org/10.1111/j.1600-0854.2007.00619.x
- ↑ Curcio-Morelli C, Zhang P, Venugopal B, Charles FA, Browning MF, Cantiello HF, Slaugenhaupt SA. Functional multimerization of mucolipin channel proteins. J Cell Physiol. 2010 Feb;222(2):328-35. doi: 10.1002/jcp.21956. PMID:19885840 doi:http://dx.doi.org/10.1002/jcp.21956
- ↑ Lev S, Zeevi DA, Frumkin A, Offen-Glasner V, Bach G, Minke B. Constitutive activity of the human TRPML2 channel induces cell degeneration. J Biol Chem. 2010 Jan 22;285(4):2771-82. doi: 10.1074/jbc.M109.046508. Epub 2009 , Nov 23. PMID:19940139 doi:http://dx.doi.org/10.1074/jbc.M109.046508
- ↑ Viet KK, Wagner A, Schwickert K, Hellwig N, Brennich M, Bader N, Schirmeister T, Morgner N, Schindelin H, Hellmich UA. Structure of the Human TRPML2 Ion Channel Extracytosolic/Lumenal Domain. Structure. 2019 May 14. pii: S0969-2126(19)30161-3. doi:, 10.1016/j.str.2019.04.016. PMID:31178222 doi:http://dx.doi.org/10.1016/j.str.2019.04.016
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