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- PDB-7lf6: Structure of lysosomal membrane protein -

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Basic information

Entry
Database: PDB / ID: 7lf6
TitleStructure of lysosomal membrane protein
ComponentsEndosomal/lysosomal potassium channel TMEM175
KeywordsMEMBRANE PROTEIN / Channel
Function / homology
Function and homology information


lysosomal lumen pH elevation / phagosome-lysosome fusion / regulation of lysosomal lumen pH / potassium ion leak channel activity / proton channel activity / arachidonate binding / potassium channel activity / potassium ion transmembrane transport / proton transmembrane transport / neuron cellular homeostasis ...lysosomal lumen pH elevation / phagosome-lysosome fusion / regulation of lysosomal lumen pH / potassium ion leak channel activity / proton channel activity / arachidonate binding / potassium channel activity / potassium ion transmembrane transport / proton transmembrane transport / neuron cellular homeostasis / lysosome / endosome membrane / endosome / lysosomal membrane
Similarity search - Function
Endosomal/lysomomal potassium channel TMEM175 / Endosomal/lysosomal potassium channel TMEM175
Similarity search - Domain/homology
Endosomal/lysosomal proton channel TMEM175
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsShen, C. / Fu, T.M. / Wang, L.F. / Rawson, S. / Wu, H.
CitationJournal: Sci Adv / Year: 2022
Title: pH regulates potassium conductance and drives a constitutive proton current in human TMEM175.
Authors: Wang Zheng / Chen Shen / Longfei Wang / Shaun Rawson / Wen Jun Xie / Carl Nist-Lund / Jason Wu / Zhangfei Shen / Shiyu Xia / Jeffrey R Holt / Hao Wu / Tian-Min Fu /
Abstract: Human TMEM175, a noncanonical potassium (K) channel in endolysosomes, contributes to their pH stability and is implicated in the pathogenesis of Parkinson's disease (PD). Structurally, the TMEM175 ...Human TMEM175, a noncanonical potassium (K) channel in endolysosomes, contributes to their pH stability and is implicated in the pathogenesis of Parkinson's disease (PD). Structurally, the TMEM175 family exhibits an architecture distinct from canonical potassium channels, as it lacks the typical TVGYG selectivity filter. Here, we show that human TMEM175 not only exhibits pH-dependent structural changes that reduce K permeation at acidic pH but also displays proton permeation. TMEM175 constitutively conducts K at pH 7.4 but displays reduced K permeation at lower pH. In contrast, proton current through TMEM175 increases with decreasing pH because of the increased proton gradient. Molecular dynamics simulation, structure-based mutagenesis, and electrophysiological analysis suggest that K ions and protons share the same permeation pathway. The M393T variant of human TMEM175 associated with PD shows reduced function in both K and proton permeation. Together, our structural and electrophysiological analysis reveals a mechanism of TMEM175 regulation by pH.
History
DepositionJan 15, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 26, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 9, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 13, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update

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Structure visualization

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Assembly

Deposited unit
A: Endosomal/lysosomal potassium channel TMEM175
B: Endosomal/lysosomal potassium channel TMEM175


Theoretical massNumber of molelcules
Total (without water)111,3342
Polymers111,3342
Non-polymers00
Water00
1


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

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Components

#1: Protein Endosomal/lysosomal potassium channel TMEM175 / Transmembrane protein 175 / hTMEM175


Mass: 55667.219 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TMEM175 / Production host: Homo sapiens (human) / References: UniProt: Q9BSA9
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: Dimer of a membrane protein / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 5.5
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 FIELD
Image recordingElectron dose: 66.5 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19_4092: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 117539 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0036442
ELECTRON MICROSCOPYf_angle_d0.6878792
ELECTRON MICROSCOPYf_dihedral_angle_d4.386860
ELECTRON MICROSCOPYf_chiral_restr0.0451086
ELECTRON MICROSCOPYf_plane_restr0.0051074

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