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==I-II linker of TRPML1 channel at pH 4.5== | ==I-II linker of TRPML1 channel at pH 4.5== | ||
<StructureSection load='5tjb' size='340' side='right' caption='[[5tjb]], [[Resolution|resolution]] 2.40Å' scene=''> | <StructureSection load='5tjb' size='340' side='right'caption='[[5tjb]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5tjb]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TJB OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[5tjb]] is a 1 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=5TJB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TJB FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4Å</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5tjb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tjb OCA], [https://pdbe.org/5tjb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tjb RCSB], [https://www.ebi.ac.uk/pdbsum/5tjb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tjb ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
[ | [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 == | ||
[ | [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;"> | |||
== Publication Abstract from PubMed == | |||
The activities of organellar ion channels are often regulated by Ca2+ and H+, which are present in high concentrations in many organelles. Here we report a structural element critical for dual Ca2+/pH regulation of TRPML1, a Ca2+-release channel crucial for endolysosomal function. TRPML1 mutations cause mucolipidosis type IV (MLIV), a severe lysosomal storage disorder characterized by neurodegeneration, mental retardation and blindness. We obtained crystal structures of the 213-residue luminal domain of human TRPML1 containing three missense MLIV-causing mutations. This domain forms a tetramer with a highly electronegative central pore formed by a novel luminal pore loop. Cysteine cross-linking and cryo-EM analyses confirmed that this architecture occurs in the full-length channel. Structure-function studies demonstrated that Ca2+ and H+ interact with the luminal pore and exert physiologically important regulation. The MLIV-causing mutations disrupt the luminal-domain structure and cause TRPML1 mislocalization. Our study reveals the structural underpinnings of TRPML1's regulation, assembly and pathogenesis. | |||
Structural basis of dual Ca2+/pH regulation of the endolysosomal TRPML1 channel.,Li M, Zhang WK, Benvin NM, Zhou X, Su D, Li H, Wang S, Michailidis IE, Tong L, Li X, Yang J Nat Struct Mol Biol. 2017 Mar;24(3):205-213. doi: 10.1038/nsmb.3362. Epub 2017, Jan 23. PMID:28112729<ref>PMID:28112729</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5tjb" style="background-color:#fffaf0;"></div> | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Benvin | [[Category: Homo sapiens]] | ||
[[Category: Li | [[Category: Large Structures]] | ||
[[Category: Li | [[Category: Benvin NM]] | ||
[[Category: Li | [[Category: Li H]] | ||
[[Category: Michailidis | [[Category: Li M]] | ||
[[Category: Su | [[Category: Li X]] | ||
[[Category: Tong | [[Category: Michailidis IE]] | ||
[[Category: Wang | [[Category: Su D]] | ||
[[Category: Yang | [[Category: Tong L]] | ||
[[Category: Zhang | [[Category: Wang S]] | ||
[[Category: Zhou | [[Category: Yang J]] | ||
[[Category: Zhang WK]] | |||
[[Category: Zhou X]] | |||
Latest revision as of 16:03, 4 October 2023
I-II linker of TRPML1 channel at pH 4.5I-II linker of TRPML1 channel at pH 4.5
Structural highlights
DiseaseMCLN1_HUMAN Mucolipidosis type 4. The disease is caused by mutations affecting the gene represented in this entry. FunctionMCLN1_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 PubMedThe activities of organellar ion channels are often regulated by Ca2+ and H+, which are present in high concentrations in many organelles. Here we report a structural element critical for dual Ca2+/pH regulation of TRPML1, a Ca2+-release channel crucial for endolysosomal function. TRPML1 mutations cause mucolipidosis type IV (MLIV), a severe lysosomal storage disorder characterized by neurodegeneration, mental retardation and blindness. We obtained crystal structures of the 213-residue luminal domain of human TRPML1 containing three missense MLIV-causing mutations. This domain forms a tetramer with a highly electronegative central pore formed by a novel luminal pore loop. Cysteine cross-linking and cryo-EM analyses confirmed that this architecture occurs in the full-length channel. Structure-function studies demonstrated that Ca2+ and H+ interact with the luminal pore and exert physiologically important regulation. The MLIV-causing mutations disrupt the luminal-domain structure and cause TRPML1 mislocalization. Our study reveals the structural underpinnings of TRPML1's regulation, assembly and pathogenesis. Structural basis of dual Ca2+/pH regulation of the endolysosomal TRPML1 channel.,Li M, Zhang WK, Benvin NM, Zhou X, Su D, Li H, Wang S, Michailidis IE, Tong L, Li X, Yang J Nat Struct Mol Biol. 2017 Mar;24(3):205-213. doi: 10.1038/nsmb.3362. Epub 2017, Jan 23. PMID:28112729[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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