|
|
| (3 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==Cryo-electron microscopy structure of a TRPML3 ion channel== | | ==Cryo-electron microscopy structure of a TRPML3 ion channel== |
| - | <StructureSection load='5w3s' size='340' side='right'caption='[[5w3s]], [[Resolution|resolution]] 2.94Å' scene=''> | + | <SX load='5w3s' size='340' side='right' viewer='molstar' caption='[[5w3s]], [[Resolution|resolution]] 2.94Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5w3s]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Calja Calja]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W3S OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5W3S FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5w3s]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Callithrix_jacchus Callithrix jacchus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W3S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5W3S FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3PE:1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE'>3PE</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.94Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MCOLN3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9483 CALJA])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3PE:1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE'>3PE</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</scene></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=5w3s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w3s OCA], [http://pdbe.org/5w3s PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5w3s RCSB], [http://www.ebi.ac.uk/pdbsum/5w3s PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5w3s ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5w3s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w3s OCA], [https://pdbe.org/5w3s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5w3s RCSB], [https://www.ebi.ac.uk/pdbsum/5w3s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5w3s ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/MCLN3_CALJA MCLN3_CALJA] Nonselective cation channel probably playing a role in the regulation of membrane trafficking events (PubMed:29019979). Acts as a Ca(2+)-permeable cation channel with inwardly rectifying activity (By similarity). 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 (By similarity). Also permeable to Mg(2+), Na(+) and K(+) (By similarity). 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. Involved in the regulation of autophagy. 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. Possible heteromeric ion channel assemblies with TRPV5 show pharmacological similarity with TRPML3 (By similarity).[UniProtKB:Q8R4F0][UniProtKB:Q8TDD5] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 20: |
Line 22: |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| - | </StructureSection> | + | </SX> |
| - | [[Category: Calja]] | + | [[Category: Callithrix jacchus]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Borschel, W F]] | + | [[Category: Borschel WF]] |
| - | [[Category: Herzik, M A]] | + | [[Category: Herzik MA]] |
| - | [[Category: Hirschi, M]] | + | [[Category: Hirschi M]] |
| - | [[Category: Lander, G C]] | + | [[Category: Lander GC]] |
| - | [[Category: Lee, S Y]] | + | [[Category: Lee SY]] |
| - | [[Category: Ren, D]] | + | [[Category: Ren D]] |
| - | [[Category: Suo, Y]] | + | [[Category: Suo Y]] |
| - | [[Category: Wie, J]] | + | [[Category: Wie J]] |
| - | [[Category: Calcium channel]]
| + | |
| - | [[Category: Ion channel]]
| + | |
| - | [[Category: Lipid-gated channel]]
| + | |
| - | [[Category: Lysosomal ion channel]]
| + | |
| - | [[Category: Lysosome]]
| + | |
| - | [[Category: Membrane transport]]
| + | |
| - | [[Category: Mucolipidosis]]
| + | |
| - | [[Category: Mucolipin]]
| + | |
| - | [[Category: Pip2]]
| + | |
| - | [[Category: Transient receptor potential channel]]
| + | |
| - | [[Category: Transport protein]]
| + | |
| - | [[Category: Trp channel]]
| + | |
| - | [[Category: Trpml]]
| + | |
| Structural highlights
Function
MCLN3_CALJA Nonselective cation channel probably playing a role in the regulation of membrane trafficking events (PubMed:29019979). Acts as a Ca(2+)-permeable cation channel with inwardly rectifying activity (By similarity). 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 (By similarity). Also permeable to Mg(2+), Na(+) and K(+) (By similarity). 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. Involved in the regulation of autophagy. 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. Possible heteromeric ion channel assemblies with TRPV5 show pharmacological similarity with TRPML3 (By similarity).[UniProtKB:Q8R4F0][UniProtKB:Q8TDD5]
Publication Abstract from PubMed
The modulation of ion channel activity by lipids is increasingly recognized as a fundamental component of cellular signalling. The transient receptor potential mucolipin (TRPML) channel family belongs to the TRP superfamily and is composed of three members: TRPML1-TRPML3. TRPMLs are the major Ca2+-permeable channels on late endosomes and lysosomes (LEL). They regulate the release of Ca2+ from organelles, which is important for various physiological processes, including organelle trafficking and fusion. Loss-of-function mutations in the MCOLN1 gene, which encodes TRPML1, cause the neurodegenerative lysosomal storage disorder mucolipidosis type IV, and a gain-of-function mutation (Ala419Pro) in TRPML3 gives rise to the varitint-waddler (Va) mouse phenotype. Notably, TRPML channels are activated by the low-abundance and LEL-enriched signalling lipid phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), whereas other phosphoinositides such as PtdIns(4,5)P2, which is enriched in plasma membranes, inhibit TRPMLs. Conserved basic residues at the N terminus of the channel are important for activation by PtdIns(3,5)P2 and inhibition by PtdIns(4,5)P2. However, owing to a lack of structural information, the mechanism by which TRPML channels recognize PtdIns(3,5)P2 and increase their Ca2+ conductance remains unclear. Here we present the cryo-electron microscopy (cryo-EM) structure of a full-length TRPML3 channel from the common marmoset (Callithrix jacchus) at an overall resolution of 2.9 A. Our structure reveals not only the molecular basis of ion conduction but also the unique architecture of TRPMLs, wherein the voltage sensor-like domain is linked to the pore via a cytosolic domain that we term the mucolipin domain. Combined with functional studies, these data suggest that the mucolipin domain is responsible for PtdIns(3,5)P2 binding and subsequent channel activation, and that it acts as a 'gating pulley' for lipid-dependent TRPML gating.
Cryo-electron microscopy structure of the lysosomal calcium-permeable channel TRPML3.,Hirschi M, Herzik MA Jr, Wie J, Suo Y, Borschel WF, Ren D, Lander GC, Lee SY Nature. 2017 Oct 19;550(7676):411-414. doi: 10.1038/nature24055. Epub 2017 Oct, 11. PMID:29019979[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hirschi M, Herzik MA Jr, Wie J, Suo Y, Borschel WF, Ren D, Lander GC, Lee SY. Cryo-electron microscopy structure of the lysosomal calcium-permeable channel TRPML3. Nature. 2017 Oct 19;550(7676):411-414. doi: 10.1038/nature24055. Epub 2017 Oct, 11. PMID:29019979 doi:http://dx.doi.org/10.1038/nature24055
|
