| Structural highlights
Function
[MCLN3_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:18369318, PubMed:19497048, PubMed:19522758, PubMed:19885840). Mediates release of Ca(2+) from endosomes to the cytoplasm, contributes to endosomal acidification and is involved in the regulation of membrane trafficking and fusion in the endosomal pathway (PubMed:21245134). Does not seem to act as mechanosensory transduction channel in inner ear sensory hair cells. Proposed to play a critical role at the cochlear stereocilia ankle-link region during hair-bundle growth (By similarity). Involved in the regulation of autophagy (PubMed:19522758). Through association with GABARAPL2 may be involved in autophagosome formation possibly providing Ca(2+) for the fusion process (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). Possible heteromeric ion channel assemblies with TRPV5 show pharmacological similarity with TRPML3 (PubMed:23469151).[UniProtKB:Q8R4F0][1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
TRPML3 channels are mainly localized to endolysosomes and play a critical role in the endocytic pathway. Their dysfunction causes deafness and pigmentation defects in mice. TRPML3 activity is inhibited by low endolysosomal pH. Here we present cryo-electron microscopy (cryo-EM) structures of human TRPML3 in the closed, agonist-activated, and low-pH-inhibited states, with resolutions of 4.06, 3.62, and 4.65 A, respectively. The agonist ML-SA1 lodges between S5 and S6 and opens an S6 gate. A polycystin-mucolipin domain (PMD) forms a luminal cap. S1 extends into this cap, forming a 'gating rod' that connects directly to a luminal pore loop, which undergoes dramatic conformational changes in response to low pH. S2 extends intracellularly and interacts with several intracellular regions to form a 'gating knob'. These unique structural features, combined with the results of electrophysiological studies, indicate a new mechanism by which luminal pH and other physiological modulators such as PIP2 regulate TRPML3 by changing S1 and S2 conformations.
Cryo-EM structures of the human endolysosomal TRPML3 channel in three distinct states.,Zhou X, Li M, Su D, Jia Q, Li H, Li X, Yang J Nat Struct Mol Biol. 2017 Nov 6. doi: 10.1038/nsmb.3502. PMID:29106414[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kim HJ, Li Q, Tjon-Kon-Sang S, So I, Kiselyov K, Soyombo AA, Muallem S. A novel mode of TRPML3 regulation by extracytosolic pH absent in the varitint-waddler phenotype. EMBO J. 2008 Apr 23;27(8):1197-205. doi: 10.1038/emboj.2008.56. Epub 2008 Mar 27. PMID:18369318 doi:http://dx.doi.org/10.1038/emboj.2008.56
- ↑ Martina JA, Lelouvier B, Puertollano R. The calcium channel mucolipin-3 is a novel regulator of trafficking along the endosomal pathway. Traffic. 2009 Aug;10(8):1143-56. Epub 2009 Apr 29. PMID:19497048 doi:http://dx.doi.org/TRA935
- ↑ Kim HJ, Soyombo AA, Tjon-Kon-Sang S, So I, Muallem S. The Ca(2+) channel TRPML3 regulates membrane trafficking and autophagy. Traffic. 2009 Aug;10(8):1157-67. doi: 10.1111/j.1600-0854.2009.00924.x. Epub 2009, May 11. PMID:19522758 doi:http://dx.doi.org/10.1111/j.1600-0854.2009.00924.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
- ↑ Lelouvier B, Puertollano R. Mucolipin-3 regulates luminal calcium, acidification, and membrane fusion in the endosomal pathway. J Biol Chem. 2011 Mar 18;286(11):9826-32. doi: 10.1074/jbc.M110.169185. Epub 2011, Jan 18. PMID:21245134 doi:http://dx.doi.org/10.1074/jbc.M110.169185
- ↑ Guo Z, Grimm C, Becker L, Ricci AJ, Heller S. A novel ion channel formed by interaction of TRPML3 with TRPV5. PLoS One. 2013;8(2):e58174. doi: 10.1371/journal.pone.0058174. Epub 2013 Feb 28. PMID:23469151 doi:http://dx.doi.org/10.1371/journal.pone.0058174
- ↑ Zhou X, Li M, Su D, Jia Q, Li H, Li X, Yang J. Cryo-EM structures of the human endolysosomal TRPML3 channel in three distinct states. Nat Struct Mol Biol. 2017 Nov 6. doi: 10.1038/nsmb.3502. PMID:29106414 doi:http://dx.doi.org/10.1038/nsmb.3502
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