5TJA
I-II linker of TRPML1 channel at pH 6
Summary for 5TJA
| Entry DOI | 10.2210/pdb5tja/pdb |
| Related | 5TJB 5TJC |
| Descriptor | Mucolipin-1 (2 entities in total) |
| Functional Keywords | endolysosomal lumen, tetramer, calcium and ph regulation, transport protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 25195.06 |
| Authors | Li, M.,Zhang, W.K.,Benvin, N.M.,Zhou, X.,Su, D.,Li, H.,Wang, S.,Michailidis, I.E.,Tong, L.,Li, X.,Yang, J. (deposition date: 2016-10-04, release date: 2017-01-25, Last modification date: 2024-10-23) |
| Primary citation | Li, M.,Zhang, W.K.,Benvin, N.M.,Zhou, X.,Su, D.,Li, H.,Wang, S.,Michailidis, I.E.,Tong, L.,Li, X.,Yang, J. Structural basis of dual Ca(2+)/pH regulation of the endolysosomal TRPML1 channel. Nat. Struct. Mol. Biol., 24:205-213, 2017 Cited by PubMed Abstract: The activities of organellar ion channels are often regulated by Ca and H, which are present in high concentrations in many organelles. Here we report a structural element critical for dual Ca/pH regulation of TRPML1, a Ca-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 Ca 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. PubMed: 28112729DOI: 10.1038/nsmb.3362 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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