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From Proteopedia
cryo-EM structure of human TRPML1 with ML-SA1 and PI35P2
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 PubMedTransient 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
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