Structural basis for PtdInsP<sub>2</sub>-mediated human TRPML1 regulation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30305615.
- Also identified by DOI 10.1038/s41467-018-06493-7 and PMC identifier 6180102.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Transient 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)P<sub>2</sub>), a natural lipid, stimulates channel activity to a lesser extent than ML-SA1; moreover, PtdIns(4,5)P<sub>2</sub>, another natural lipid, prevents TRPML1-mediated calcium release. Notably, PtdIns(3,5)P<sub>2</sub> and ML-SA1 cooperate further increasing calcium efflux. Here we report the structures of human TRPML1 at pH 5.0 with PtdIns(3,5)P<sub>2</sub>, PtdIns(4,5)P<sub>2</sub>, or ML-SA1 and PtdIns(3,5)P<sub>2</sub>, revealing a unique lipid-binding site. PtdIns(3,5)P<sub>2</sub> and PtdIns(4,5)P<sub>2</sub> bind to the extended helices of S1, S2, and S3. The phosphate group of PtdIns(3,5)P<sub>2</sub> induces Y355 to form a π-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.
Medical subject headings
- Phosphatidylinositol 4,5-Diphosphate
- Phosphatidylinositol Phosphates
- Transient Receptor Potential Channels