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5wpt

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Revision as of 22:27, 10 April 2020

Cryo-EM structure of mammalian endolysosomal TRPML1 channel in nanodiscs in closed II conformation at 3.75 Angstrom resolution

5wpt, resolution 3.75Å

Structural highlights

5wpt is a 4 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	5wpo, 5wpq, 5wpv
Gene:	Mcoln1 (LK3 transgenic mice)
Experimental data:	Check to display Experimental Data
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[MCLN1_MOUSE] Nonselective cation channel probably playing a role in the regulation of membrane trafficking events and of metal homeostasis. Proposed to play a major role in Ca(2+) release from late endosome and lysosome vesicles to the cytoplasm, which is important for many lysosome-dependent cellular events, including the fusion and trafficking of these organelles, exocytosis and autophagy. Required for efficient uptake of large particles in macrophages in which Ca(2+) release from the lysosomes triggers lysosomal exocytosis. May also play a role in phagosome-lysosome fusion (PubMed:23993788). Involved in lactosylceramide trafficking indicative for a role in the regulation of late endocytic membrane fusion/fission events. By mediating lysosomal Ca(2+) release is involved in regulation of mTORC1 signaling and in mTOR/TFEB-dependent lysosomal adaptation to environmental cues such as nutrient levels (PubMed:25733853). Seems to act as lysosomal active oxygen species (ROS) sensor involved in ROS-induced TFEB activation and autophagy (By similarity). Functions as a Fe(2+) permeable channel in late endosomes and lysosomes. Proposed to play a role in zinc homeostasis probably implicating its association with TMEM163 (By similarity). In adaptive immunity, TRPML2 and TRPML1 may play redundant roles in the function of the specialized lysosomes of B cells (PubMed:17050035).[UniProtKB:Q9GZU1]^[1] ^[2] ^[3] May contribute to cellular lipase activity within the late endosomal pathway or at the cell surface which may be involved in processes of membrane reshaping and vesiculation, especially the growth of tubular structures. However, it is not known, whether it conveys the enzymatic activity directly, or merely facilitates the activity of an associated phospholipase.[UniProtKB:Q9GZU1]

Publication Abstract from PubMed

Transient receptor potential mucolipin 1 (TRPML1) is a cation channel located within endosomal and lysosomal membranes. Ubiquitously expressed in mammalian cells, its loss-of-function mutations are the direct cause of type IV mucolipidosis, an autosomal recessive lysosomal storage disease. Here we present the single-particle electron cryo-microscopy structure of the mouse TRPML1 channel embedded in nanodiscs. Combined with mutagenesis analysis, the TRPML1 structure reveals that phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2) binds to the N terminus of the channel-distal from the pore-and the helix-turn-helix extension between segments S2 and S3 probably couples ligand binding to pore opening. The tightly packed selectivity filter contains multiple ion-binding sites, and the conserved acidic residues form the luminal Ca2+-blocking site that confers luminal pH and Ca2+ modulation on channel conductance. A luminal linker domain forms a fenestrated canopy atop the channel, providing several luminal ion passages to the pore and creating a negative electrostatic trap, with a preference for divalent cations, at the luminal entrance. The structure also reveals two equally distributed S4-S5 linker conformations in the closed channel, suggesting an S4-S5 linker-mediated PtdInsP2 gating mechanism among TRPML channels.

Structure of mammalian endolysosomal TRPML1 channel in nanodiscs.,Chen Q, She J, Zeng W, Guo J, Xu H, Bai XC, Jiang Y Nature. 2017 Oct 19;550(7676):415-418. doi: 10.1038/nature24035. Epub 2017 Oct, 11. PMID:29019981^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Song Y, Dayalu R, Matthews SA, Scharenberg AM. TRPML cation channels regulate the specialized lysosomal compartment of vertebrate B-lymphocytes. Eur J Cell Biol. 2006 Dec;85(12):1253-64. Epub 2006 Oct 16. PMID:17050035 doi:http://dx.doi.org/10.1016/j.ejcb.2006.08.004
↑ Samie M, Wang X, Zhang X, Goschka A, Li X, Cheng X, Gregg E, Azar M, Zhuo Y, Garrity AG, Gao Q, Slaugenhaupt S, Pickel J, Zolov SN, Weisman LS, Lenk GM, Titus S, Bryant-Genevier M, Southall N, Juan M, Ferrer M, Xu H. A TRP channel in the lysosome regulates large particle phagocytosis via focal exocytosis. Dev Cell. 2013 Sep 16;26(5):511-24. doi: 10.1016/j.devcel.2013.08.003. Epub 2013 , Aug 29. PMID:23993788 doi:http://dx.doi.org/10.1016/j.devcel.2013.08.003
↑ Wang W, Gao Q, Yang M, Zhang X, Yu L, Lawas M, Li X, Bryant-Genevier M, Southall NT, Marugan J, Ferrer M, Xu H. Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation. Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):E1373-81. doi:, 10.1073/pnas.1419669112. Epub 2015 Mar 2. PMID:25733853 doi:http://dx.doi.org/10.1073/pnas.1419669112
↑ Chen Q, She J, Zeng W, Guo J, Xu H, Bai XC, Jiang Y. Structure of mammalian endolysosomal TRPML1 channel in nanodiscs. Nature. 2017 Oct 19;550(7676):415-418. doi: 10.1038/nature24035. Epub 2017 Oct, 11. PMID:29019981 doi:http://dx.doi.org/10.1038/nature24035

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5wpt"

@@ Line 3: / Line 3: @@
 <SX load='5wpt' size='340' side='right' viewer='molstar' caption='[[5wpt]], [[Resolution|resolution]] 3.75&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5wpt]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WPT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WPT FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5wpt]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WPT OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5WPT FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5wpo|5wpo]], [[5wpq|5wpq]], [[5wpv|5wpv]]</td></tr>
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Mcoln1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5wpt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wpt OCA], [http://pdbe.org/5wpt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wpt RCSB], [http://www.ebi.ac.uk/pdbsum/5wpt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wpt ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5wpt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wpt OCA], [http://pdbe.org/5wpt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wpt RCSB], [http://www.ebi.ac.uk/pdbsum/5wpt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wpt ProSAT]</span></td></tr>
 </table>
 == Function ==

5wpt

From Proteopedia

Revision as of 22:27, 10 April 2020

Cryo-EM structure of mammalian endolysosomal TRPML1 channel in nanodiscs in closed II conformation at 3.75 Angstrom resolution

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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