5tjb

I-II linker of TRPML1 channel at pH 4.5

spinqualitylabelsall models 5tjb, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5tjb is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.4Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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