biostudies-literatureUnknownGan NNIGMS NIH HHSTransient Receptor Potential Mucolipin 1 (TRPML1) is a lysosomal cation channel whose loss-of-function mutations directly cause the lysosomal storage disorder mucolipidosis type IV (MLIV). TRPML1 can be allosterically regulated by various ligands including natural lipids and small synthetic molecules and the channel undergoes a global movement propagated from ligand-induced local conformational changes upon activation. In this study, we identified a functionally critical residue, Tyr404, at the C-terminus of the S4 helix, whose mutations to tryptophan and alanine yield gain- and loss-of-function channels, respectively. These allosteric mutations mimic the ligand activation or inhibition of the TRPML1 channel without interfering with ligand binding and both mutant channels are susceptible tbioRxiv : the preprint server for biology2024.07.04.602033https://www.ebi.ac.uk/biostudies/studies/S-EPMC11245044biostudies-literatureTRPML1 gating modulation by allosteric mutations and lipids.PMC11245044R35 GM140892Jiang YGan NHan YZeng WfalseTRPML1 gating modulation by allosteric mutations and lipids.Transient Receptor Potential Mucolipin 1 (TRPML1) is a lysosomal cation channel whose loss-of-function mutations directly cause the lysosomal storage disorder mucolipidosis type IV (MLIV). TRPML1 can be allosterically regulated by various ligands including natural lipids and small synthetic molecules and the channel undergoes a global movement propagated from ligand-induced local conformational changes upon activation. In this study, we identified a functionally critical residue, Tyr404, at the C-terminus of the S4 helix, whose mutations to tryptophan and alanine yield gain- and loss-of-function channels, respectively. These allosteric mutations mimic the ligand activation or inhibition of the TRPML1 channel without interfering with ligand binding and both mutant channels are susceptible t2024-01-01T00:00:00Z2024 Sep2026-05-26T20:04:30.975Z2025-04-21T21:41:44.671ZS-EPMC112450443900534910.1101/2024.07.04.602033