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- PDB-6e7y: cryo-EM structure of human TRPML1 with PI45P2 -

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Basic information

Entry
Database: PDB / ID: 6e7y
Titlecryo-EM structure of human TRPML1 with PI45P2
ComponentsMucolipin-1MCOLN1
KeywordsMEMBRANE PROTEIN / human TRPML1
Function / homology
Function and homology information


calcium ion export / positive regulation of lysosome organization / iron ion transmembrane transporter activity / intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity / NAADP-sensitive calcium-release channel activity / phagosome maturation / transferrin transport / Transferrin endocytosis and recycling / cellular response to pH / ligand-gated calcium channel activity ...calcium ion export / positive regulation of lysosome organization / iron ion transmembrane transporter activity / intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity / NAADP-sensitive calcium-release channel activity / phagosome maturation / transferrin transport / Transferrin endocytosis and recycling / cellular response to pH / ligand-gated calcium channel activity / TRP channels / phagocytic cup / autophagosome maturation / monoatomic cation transport / localization / monoatomic cation channel activity / release of sequestered calcium ion into cytosol / cellular response to calcium ion / cell projection / calcium ion transmembrane transport / calcium channel activity / phagocytic vesicle membrane / late endosome / late endosome membrane / protein homotetramerization / adaptive immune response / lysosome / receptor complex / endosome membrane / lysosomal membrane / intracellular membrane-bounded organelle / lipid binding / Golgi apparatus / nucleoplasm / membrane / identical protein binding / plasma membrane
Similarity search - Function
: / : / Mucolipin, extracytosolic domain / Mucolipin / Polycystin cation channel, PKD1/PKD2 / Polycystin cation channel
Similarity search - Domain/homology
Chem-PIO / Mucolipin-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.57 Å
AuthorsSchmiege, P. / Li, X.
CitationJournal: Nat Commun / Year: 2018
Title: Structural basis for PtdInsP-mediated human TRPML1 regulation.
Authors: Michael Fine / Philip Schmiege / Xiaochun Li /
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 ...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.
History
DepositionJul 27, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 28, 2018Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
A: Mucolipin-1
B: Mucolipin-1
C: Mucolipin-1
D: Mucolipin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)263,3268
Polymers260,3404
Non-polymers2,9864
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Mucolipin-1 / MCOLN1 / ML1 / MG-2 / Mucolipidin / Transient receptor potential channel mucolipin 1 / TRPML1


Mass: 65084.996 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MCOLN1, ML4, MSTP080 / Production host: Homo sapiens (human) / References: UniProt: Q9GZU1
#2: Chemical
ChemComp-PIO / [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate / dioctanoyl l-alpha-phosphatidyl-d-myo-inositol 4,5-diphosphate


Mass: 746.566 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H49O19P3

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: TRPML1MCOLN1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7
SpecimenConc.: 7 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
VitrificationCryogen name: NITROGEN

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 1.6 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.13_2998: / Classification: refinement
EM software
IDNameCategory
1RELIONparticle selection
4CTFFINDCTF correction
13FREALIX3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.57 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 69587 / Symmetry type: POINT
RefinementHighest resolution: 3.57 Å
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00315896
ELECTRON MICROSCOPYf_angle_d0.76921580
ELECTRON MICROSCOPYf_dihedral_angle_d11.0079304
ELECTRON MICROSCOPYf_chiral_restr0.0482460
ELECTRON MICROSCOPYf_plane_restr0.0062656

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