Journal Article

Structural basis for PtdInsP 2 -mediated human TRPML1 regulation

Li, Xiaochun, Fine, Michael, Schmiege, Philip

2018

Overview

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 ), a natural lipid, stimulates channel activity to a lesser extent than ML-SA1; moreover, PtdIns(4,5)P , another natural lipid, prevents TRPML1-mediated calcium release. Notably, PtdIns(3,5)P 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 , PtdIns(4,5)P , or ML-SA1 and PtdIns(3,5)P , revealing a unique lipid-binding site. PtdIns(3,5)P and PtdIns(4,5)P bind to the extended helices of S1, S2, and S3. The phosphate group of PtdIns(3,5)P 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.

• Subject: Amino Acid Sequence / Cryoelectron Microscopy / Humans / Ion Channel Gating / Ligands / Mutation - genetics / Phosphatidylinositol 4,5-Diphosphate - chemistry / Phosphatidylinositol 4,5-Diphosphate - metabolism / Phosphatidylinositol Phosphates - chemistry / Phosphatidylinositol Phosphates - metabolism / Phthalimides - pharmacology / Quinolines - pharmacology / Reproducibility of Results / Transient Receptor Potential Channels - chemistry / Transient Receptor Potential Channels - metabolism / Transient Receptor Potential Channels - ultrastructure