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-Structure paper
タイトル | Structural basis for PtdInsP-mediated human TRPML1 regulation. |
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ジャーナル・号・ページ | Nat Commun, Vol. 9, Issue 1, Page 4192, Year 2018 |
掲載日 | 2018年10月10日 |
![]() | Michael Fine / Philip Schmiege / Xiaochun Li / ![]() |
PubMed 要旨 | 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 ...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. |
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手法 | EM (単粒子) |
解像度 | 3.5 - 3.73 Å |
構造データ | |
化合物 | ![]() ChemComp-HZ7: ![]() ChemComp-PIO: ![]() ChemComp-AQV: |
由来 |
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![]() | MEMBRANE PROTEIN / human TRPML1 |