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- PDB-9cc2: Cryo-EM structure of mouse PI(4,5)P2-bound TRPML1 channel at 2.46... -

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Basic information

Entry
Database: PDB / ID: 9cc2
TitleCryo-EM structure of mouse PI(4,5)P2-bound TRPML1 channel at 2.46 Angstrom resolution
ComponentsMucolipin-1
KeywordsMEMBRANE PROTEIN / TRPML1
Function / homology
Function and homology information


Transferrin endocytosis and recycling / positive regulation of lysosome organization / calcium ion export / intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity / phagosome maturation / NAADP-sensitive calcium-release channel activity / iron ion transmembrane transporter activity / cellular response to pH / iron ion transmembrane transport / TRP channels ...Transferrin endocytosis and recycling / positive regulation of lysosome organization / calcium ion export / intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity / phagosome maturation / NAADP-sensitive calcium-release channel activity / iron ion transmembrane transporter activity / cellular response to pH / iron ion transmembrane transport / TRP channels / monoatomic anion channel activity / endosomal transport / intracellular vesicle / sodium channel activity / monoatomic cation transmembrane transport / autophagosome maturation / potassium channel activity / phagocytic cup / monoatomic cation channel activity / release of sequestered calcium ion into cytosol / cellular response to calcium ion / cell projection / calcium channel activity / phagocytic vesicle membrane / late endosome membrane / late endosome / protein homotetramerization / adaptive immune response / lysosome / receptor complex / lysosomal membrane / lipid binding / Golgi apparatus / nucleoplasm / identical protein binding / membrane
Similarity search - Function
: / Mucolipin / : / Mucolipin, extracytosolic domain / Polycystin cation channel, PKD1/PKD2 / Polycystin cation channel
Similarity search - Domain/homology
sphingomyelin / Chem-PIO / Mucolipin-1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.46 Å
AuthorsGan, N. / Jiang, Y.
Funding support United States, 3items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM140892 United States
Welch FoundationI-1578 United States
CitationJournal: bioRxiv / Year: 2024
Title: TRPML1 gating modulation by allosteric mutations and lipids.
Authors: Ninghai Gan / Yan Han / Weizhong Zeng / Youxing Jiang /
Abstract: Transient Receptor Potential Mucolipin 1 (TRPML1) is a lysosomal cation channel whose loss-of-function mutations directly cause the lysosomal storage disorder mucolipidosis type IV (MLIV). TRPML1 can ...Transient Receptor Potential Mucolipin 1 (TRPML1) is a lysosomal cation channel whose loss-of-function mutations directly cause the lysosomal storage disorder mucolipidosis type IV (MLIV). TRPML1 can be allosterically regulated by various ligands including natural lipids and small synthetic molecules and the channel undergoes a global movement propagated from ligand-induced local conformational changes upon activation. In this study, we identified a functionally critical residue, Tyr404, at the C-terminus of the S4 helix, whose mutations to tryptophan and alanine yield gain- and loss-of-function channels, respectively. These allosteric mutations mimic the ligand activation or inhibition of the TRPML1 channel without interfering with ligand binding and both mutant channels are susceptible to agonist or antagonist modulation, making them better targets for screening potent TRPML1 activators and inhibitors. We also determined the high-resolution structure of TRPML1 in complex with the PI(4,5)P inhibitor, revealing the structural basis underlying this lipid inhibition. In addition, an endogenous phospholipid likely from sphingomyelin is identified in the PI(4,5)P-bound TRPML1 structure at the same hotspot for agonists and antagonists, providing a plausible structural explanation for the inhibitory effect of sphingomyelin on agonist activation.
History
DepositionJun 20, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 9, 2024Provider: repository / Type: Initial release
Revision 1.0Oct 9, 2024Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
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Revision 1.1Nov 6, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update
Revision 1.2Jun 4, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jun 4, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)270,23516
Polymers262,2944
Non-polymers7,94112
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Mucolipin-1 / Mucolipidin / Transient receptor potential-mucolipin 1 / TRPML1


Mass: 65573.617 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Mcoln1, Trpml1 / Production host: Homo sapiens (human) / References: UniProt: Q99J21
#2: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#3: 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 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-FO4 / sphingomyelin


Mass: 814.233 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C47H94N2O6P / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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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: mouse TRPML1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: DIFFRACTION / Nominal defocus max: 2200 nm / Nominal defocus min: 900 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.46 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 60597 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00215916
ELECTRON MICROSCOPYf_angle_d0.44921540
ELECTRON MICROSCOPYf_dihedral_angle_d11.6572484
ELECTRON MICROSCOPYf_chiral_restr0.0392476
ELECTRON MICROSCOPYf_plane_restr0.0032596

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