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- EMDB-8841: cryo-EM of a lysosomal protein -

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Basic information

Entry
Database: EMDB / ID: EMD-8841
Titlecryo-EM of a lysosomal protein
Map data
Sample
  • Complex: TRPML1
    • Protein or peptide: Mucolipin-1
  • Ligand: 2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione
Keywordshuman TRPML1 / MEMBRANE PROTEIN
Function / homology
Function and homology information


calcium ion export / positive regulation of lysosome organization / intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity / phagosome maturation / NAADP-sensitive calcium-release channel activity / iron ion transmembrane transporter activity / transferrin transport / iron ion transmembrane transport / Transferrin endocytosis and recycling / cellular response to pH ...calcium ion export / positive regulation of lysosome organization / intracellularly phosphatidylinositol-3,5-bisphosphate-gated monatomic cation channel activity / phagosome maturation / NAADP-sensitive calcium-release channel activity / iron ion transmembrane transporter activity / transferrin transport / iron ion transmembrane transport / Transferrin endocytosis and recycling / cellular response to pH / monoatomic anion channel activity / ligand-gated calcium channel activity / TRP channels / sodium channel activity / monoatomic cation transport / phagocytic cup / potassium channel activity / autophagosome maturation / 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 / identical protein binding / membrane / plasma membrane
Similarity search - Function
: / Mucolipin / : / Mucolipin, extracytosolic domain / Polycystin cation channel, PKD1/PKD2 / Polycystin cation channel
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.49 Å
AuthorsSchmiege P / Li X
CitationJournal: Nature / Year: 2017
Title: Human TRPML1 channel structures in open and closed conformations.
Authors: Philip Schmiege / Michael Fine / Günter Blobel / Xiaochun Li /
Abstract: Transient receptor potential mucolipin 1 (TRPML1) is a Ca-releasing cation channel that mediates the calcium signalling and homeostasis of lysosomes. Mutations in TRPML1 lead to mucolipidosis type ...Transient receptor potential mucolipin 1 (TRPML1) is a Ca-releasing cation channel that mediates the calcium signalling and homeostasis of lysosomes. Mutations in TRPML1 lead to mucolipidosis type IV, a severe lysosomal storage disorder. Here we report two electron cryo-microscopy structures of full-length human TRPML1: a 3.72-Å apo structure at pH 7.0 in the closed state, and a 3.49-Å agonist-bound structure at pH 6.0 in an open state. Several aromatic and hydrophobic residues in pore helix 1, helices S5 and S6, and helix S6 of a neighbouring subunit, form a hydrophobic cavity to house the agonist, suggesting a distinct agonist-binding site from that found in TRPV1, a TRP channel from a different subfamily. The opening of TRPML1 is associated with distinct dilations of its lower gate together with a slight structural movement of pore helix 1. Our work reveals the regulatory mechanism of TRPML channels, facilitates better understanding of TRP channel activation, and provides insights into the molecular basis of mucolipidosis type IV pathogenesis.
History
DepositionJul 21, 2017-
Header (metadata) releaseAug 9, 2017-
Map releaseOct 18, 2017-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 1.3
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 1.3
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-5wj9
  • Surface level: 1.3
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_8841.png

Downloads & links

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Map

FileDownload / File: emd_8841.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1 Å/pix.
x 300 pix.
= 300. Å		1 Å/pix.
x 300 pix.
= 300. Å		1 Å/pix.
x 300 pix.
= 300. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.3 / Movie #1: 1.3
Minimum - Maximum-2.7395012 - 4.9342475
Average (Standard dev.)0.015026407 (±0.18624455)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 300.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z111
M x/y/z300300300
origin x/y/z0.0000.0000.000
length x/y/z300.000300.000300.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-2.7404.9340.015

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Supplemental data

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Sample components

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Entire : TRPML1

EntireName: TRPML1
Components
  • Complex: TRPML1
    • Protein or peptide: Mucolipin-1
  • Ligand: 2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione

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Supramolecule #1: TRPML1

SupramoleculeName: TRPML1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Mucolipin-1

MacromoleculeName: Mucolipin-1 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 65.084996 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MTAPAGPRGS ETERLLTPNP GYGTQAGPSP APPTPPEEED LRRRLKYFFM SPCDKFRAKG RKPCKLMLQV VKILVVTVQL ILFGLSNQL AVTFREENTI AFRHLFLLGY SDGADDTFAA YTREQLYQAI FHAVDQYLAL PDVSLGRYAY VRGGGDPWTN G SGLALCQR ...String:
MTAPAGPRGS ETERLLTPNP GYGTQAGPSP APPTPPEEED LRRRLKYFFM SPCDKFRAKG RKPCKLMLQV VKILVVTVQL ILFGLSNQL AVTFREENTI AFRHLFLLGY SDGADDTFAA YTREQLYQAI FHAVDQYLAL PDVSLGRYAY VRGGGDPWTN G SGLALCQR YYHRGHVDPA NDTFDIDPMV VTDCIQVDPP ERPPPPPSDD LTLLESSSSY KNLTLKFHKL VNVTIHFRLK TI NLQSLIN NEIPDCYTFS VLITFDNKAH SGRIPISLET QAHIQECKHP SVFQHGDNSF RLLFDVVVIL TCSLSFLLCA RSL LRGFLL QNEFVGFMWR QRGRVISLWE RLEFVNGWYI LLVTSDVLTI SGTIMKIGIE AKNLASYDVC SILLGTSTLL VWVG VIRYL TFFHNYNILI ATLRVALPSV MRFCCCVAVI YLGYCFCGWI VLGPYHVKFR SLSMVSECLF SLINGDDMFV TFAAM QAQQ GRSSLVWLFS QLYLYSFISL FIYMVLSLFI ALITGAYDTI KHPGGAGAEE SELQAYIAQC QDSPTSGKFR RGSGSA CSL LCCCGRDPSE EHSLLVN

UniProtKB: Mucolipin-1

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Macromolecule #2: 2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]eth...

MacromoleculeName: 2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione
type: ligand / ID: 2 / Number of copies: 4 / Formula: AQV
Molecular weightTheoretical: 362.422 Da
Chemical component information

ChemComp-AQV:
2-{2-oxo-2-[(4S)-2,2,4-trimethyl-3,4-dihydroquinolin-1(2H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration7 mg/mL
BufferpH: 7
VitrificationCryogen name: NITROGEN

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 1.6 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

6670

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.49 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: FREALIGN / Number images used: 56105
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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