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| | <SX load='6e7y' size='340' side='right' viewer='molstar' caption='[[6e7y]], [[Resolution|resolution]] 3.57Å' scene=''> | | <SX load='6e7y' size='340' side='right' viewer='molstar' caption='[[6e7y]], [[Resolution|resolution]] 3.57Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6e7y]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E7Y OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6E7Y FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6e7y]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6E7Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6E7Y FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PIO:[(2R)-2-OCTANOYLOXY-3-[OXIDANYL-[(1R,2R,3S,4R,5R,6S)-2,3,6-TRIS(OXIDANYL)-4,5-DIPHOSPHONOOXY-CYCLOHEXYL]OXY-PHOSPHORYL]OXY-PROPYL]+OCTANOATE'>PIO</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]] 3.57Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MCOLN1, ML4, MSTP080 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PIO:[(2R)-2-OCTANOYLOXY-3-[OXIDANYL-[(1R,2R,3S,4R,5R,6S)-2,3,6-TRIS(OXIDANYL)-4,5-DIPHOSPHONOOXY-CYCLOHEXYL]OXY-PHOSPHORYL]OXY-PROPYL]+OCTANOATE'>PIO</scene></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=6e7y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e7y OCA], [http://pdbe.org/6e7y PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6e7y RCSB], [http://www.ebi.ac.uk/pdbsum/6e7y PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6e7y 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=6e7y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e7y OCA], [https://pdbe.org/6e7y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6e7y RCSB], [https://www.ebi.ac.uk/pdbsum/6e7y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6e7y ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/MCLN1_HUMAN MCLN1_HUMAN]] Mucolipidosis type 4. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/MCLN1_HUMAN MCLN1_HUMAN] Mucolipidosis type 4. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MCLN1_HUMAN MCLN1_HUMAN]] Cation channel probably playing a role in the endocytic pathway and in the control of membrane trafficking of proteins and lipids. Could play a major role in Ca(2+) transport regulating lysosomal exocytosis.<ref>PMID:12459486</ref> <ref>PMID:14749347</ref> | + | [https://www.uniprot.org/uniprot/MCLN1_HUMAN MCLN1_HUMAN] Cation channel probably playing a role in the endocytic pathway and in the control of membrane trafficking of proteins and lipids. Could play a major role in Ca(2+) transport regulating lysosomal exocytosis.<ref>PMID:12459486</ref> <ref>PMID:14749347</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </SX> | | </SX> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Li, X]] | + | [[Category: Li X]] |
| - | [[Category: Schmiege, P]] | + | [[Category: Schmiege P]] |
| - | [[Category: Human trpml1]]
| + | |
| - | [[Category: Membrane protein]]
| + | |
| Structural highlights
Disease
MCLN1_HUMAN Mucolipidosis type 4. The disease is caused by mutations affecting the gene represented in this entry.
Function
MCLN1_HUMAN Cation channel probably playing a role in the endocytic pathway and in the control of membrane trafficking of proteins and lipids. Could play a major role in Ca(2+) transport regulating lysosomal exocytosis.[1] [2]
Publication Abstract from PubMed
Transient receptor potential mucolipin 1 (TRPML1), a lysosomal channel, maintains the low pH and calcium levels for lysosomal function. Several small molecules modulate TRPML1 activity. ML-SA1, a synthetic agonist, binds to the pore region and phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), a natural lipid, stimulates channel activity to a lesser extent than ML-SA1; moreover, PtdIns(4,5)P2, another natural lipid, prevents TRPML1-mediated calcium release. Notably, PtdIns(3,5)P2 and ML-SA1 cooperate further increasing calcium efflux. Here we report the structures of human TRPML1 at pH 5.0 with PtdIns(3,5)P2, PtdIns(4,5)P2, or ML-SA1 and PtdIns(3,5)P2, revealing a unique lipid-binding site. PtdIns(3,5)P2 and PtdIns(4,5)P2 bind to the extended helices of S1, S2, and S3. The phosphate group of PtdIns(3,5)P2 induces Y355 to form a pi-cation interaction with R403, moving the S4-S5 linker, thus allosterically activating the channel. Our structures and electrophysiological characterizations reveal an allosteric site and provide molecular insight into how lipids regulate TRP channels.
Structural basis for PtdInsP2-mediated human TRPML1 regulation.,Fine M, Schmiege P, Li X Nat Commun. 2018 Oct 10;9(1):4192. doi: 10.1038/s41467-018-06493-7. PMID:30305615[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ LaPlante JM, Falardeau J, Sun M, Kanazirska M, Brown EM, Slaugenhaupt SA, Vassilev PM. Identification and characterization of the single channel function of human mucolipin-1 implicated in mucolipidosis type IV, a disorder affecting the lysosomal pathway. FEBS Lett. 2002 Dec 4;532(1-2):183-7. PMID:12459486
- ↑ Raychowdhury MK, Gonzalez-Perrett S, Montalbetti N, Timpanaro GA, Chasan B, Goldmann WH, Stahl S, Cooney A, Goldin E, Cantiello HF. Molecular pathophysiology of mucolipidosis type IV: pH dysregulation of the mucolipin-1 cation channel. Hum Mol Genet. 2004 Mar 15;13(6):617-27. Epub 2004 Jan 28. PMID:14749347 doi:http://dx.doi.org/10.1093/hmg/ddh067
- ↑ Fine M, Schmiege P, Li X. Structural basis for PtdInsP2-mediated human TRPML1 regulation. Nat Commun. 2018 Oct 10;9(1):4192. doi: 10.1038/s41467-018-06493-7. PMID:30305615 doi:http://dx.doi.org/10.1038/s41467-018-06493-7
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