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- PDB-7sq8: Cryo-EM structure of mouse apo TRPML1 channel at 2.598 Angstrom r... -

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Basic information

Entry
Database: PDB / ID: 7sq8
TitleCryo-EM structure of mouse apo TRPML1 channel at 2.598 Angstrom resolution
ComponentsMucolipin-1MCOLN1
KeywordsMEMBRANE PROTEIN / ion channel
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 / cellular response to pH / ligand-gated calcium channel activity / TRP channels / endosomal transport ...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 / cellular response to pH / ligand-gated calcium channel activity / TRP channels / endosomal transport / phagocytic cup / intracellular vesicle / autophagosome maturation / monoatomic cation transmembrane transport / localization / release of sequestered calcium ion into cytosol / monoatomic cation channel activity / cellular response to calcium ion / cell projection / calcium ion transmembrane transport / phagocytic vesicle membrane / late endosome / late endosome membrane / protein homotetramerization / adaptive immune response / lysosome / receptor complex / 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
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.598 Å
AuthorsGan, N. / Han, Y. / Jiang, Y.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM140892
Welch FoundationI-1578 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
Title: Structural mechanism of allosteric activation of TRPML1 by PI(3,5)P and rapamycin.
Authors: Ninghai Gan / Yan Han / Weizhong Zeng / Yan Wang / Jing Xue / Youxing Jiang /
Abstract: Transient receptor potential mucolipin 1 (TRPML1) is a Ca-permeable, nonselective cation channel ubiquitously expressed in the endolysosomes of mammalian cells and its loss-of-function mutations are ...Transient receptor potential mucolipin 1 (TRPML1) is a Ca-permeable, nonselective cation channel ubiquitously expressed in the endolysosomes of mammalian cells and its loss-of-function mutations are the direct cause of type IV mucolipidosis (MLIV), an autosomal recessive lysosomal storage disease. TRPML1 is a ligand-gated channel that can be activated by phosphatidylinositol 3,5-bisphosphate [PI(3,5)P] as well as some synthetic small-molecule agonists. Recently, rapamycin has also been shown to directly bind and activate TRPML1. Interestingly, both PI(3,5)P and rapamycin have low efficacy in channel activation individually but together they work cooperatively and activate the channel with high potency. To reveal the structural basis underlying the synergistic activation of TRPML1 by PI(3,5)P and rapamycin, we determined the high-resolution cryoelectron microscopy (cryo-EM) structures of the mouse TRPML1 channel in various states, including apo closed, PI(3,5)P-bound closed, and PI(3,5)P/temsirolimus (a rapamycin analog)-bound open states. These structures, combined with electrophysiology, elucidate the molecular details of ligand binding and provide structural insight into how the TRPML1 channel integrates two distantly bound ligand stimuli and facilitates channel opening.
History
DepositionNov 4, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 2, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 16, 2022Group: Data collection / Database references / Category: citation / citation_author / em_image_recording
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _em_image_recording.avg_electron_dose_per_image
Revision 1.2Feb 23, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation.title

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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)264,0159
Polymers262,2944
Non-polymers1,7215
Water1448
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Mucolipin-1 / MCOLN1 / 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-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 8 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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 Transient receptor potential-mucolipin 1 apo closed state
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: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2200 nm / Nominal defocus min: 900 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 2.598 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 33553 / Symmetry type: POINT

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