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- PDB-8fy5: Human TMEM175-LAMP1 full-length complex -

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Basic information

Entry
Database: PDB / ID: 8fy5
TitleHuman TMEM175-LAMP1 full-length complex
Components
  • Endosomal/lysosomal potassium channel TMEM175
  • Lysosome-associated membrane glycoprotein 1
KeywordsMEMBRANE PROTEIN / Complex
Function / homology
Function and homology information


regulation of organelle transport along microtubule / positive regulation of natural killer cell degranulation / lysosomal lumen pH elevation / granzyme-mediated programmed cell death signaling pathway / phagolysosome membrane / phagosome-lysosome fusion / Golgi to lysosome transport / cytolytic granule membrane / establishment of protein localization to organelle / regulation of lysosomal lumen pH ...regulation of organelle transport along microtubule / positive regulation of natural killer cell degranulation / lysosomal lumen pH elevation / granzyme-mediated programmed cell death signaling pathway / phagolysosome membrane / phagosome-lysosome fusion / Golgi to lysosome transport / cytolytic granule membrane / establishment of protein localization to organelle / regulation of lysosomal lumen pH / potassium ion leak channel activity / lysosomal lumen acidification / positive regulation of natural killer cell mediated cytotoxicity / proton channel activity / arachidonate binding / azurophil granule membrane / ion channel inhibitor activity / autolysosome / autophagosome membrane / ficolin-1-rich granule membrane / potassium channel activity / potassium ion transmembrane transport / multivesicular body / proton transmembrane transport / sarcolemma / neuron cellular homeostasis / late endosome membrane / late endosome / melanosome / synaptic vesicle / virus receptor activity / lysosome / protein stabilization / endosome / endosome membrane / protein domain specific binding / lysosomal membrane / external side of plasma membrane / Neutrophil degranulation / perinuclear region of cytoplasm / enzyme binding / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Lysosome-associated membrane glycoprotein, conserved site / : / Lysosome-associated membrane glycoprotein 2, transmembrane segment / Lysosome-associated membrane glycoproteins duplicated domain signature. / LAMP glycoproteins transmembrane and cytoplasmic domain signature. / Lysosome-associated membrane glycoprotein / : / Lysosome-associated membrane glycoprotein 2-like, luminal domains / Lysosome-associated membrane glycoprotein family profile. / Endosomal/lysomomal potassium channel TMEM175 / Endosomal/lysosomal potassium channel TMEM175
Similarity search - Domain/homology
Lysosome-associated membrane glycoprotein 1 / Endosomal/lysosomal proton channel TMEM175
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsZhang, J.Y. / Zeng, W.Z. / Han, Y. / Jiang, Y.X.
Funding support United States, 1items
OrganizationGrant numberCountry
Department of Health & Human Services (HHS)R35GM140892 United States
CitationJournal: Mol Cell / Year: 2023
Title: Lysosomal LAMP proteins regulate lysosomal pH by direct inhibition of the TMEM175 channel.
Authors: Jiyuan Zhang / Weizhong Zeng / Yan Han / Wan-Ru Lee / Jen Liou / Youxing Jiang /
Abstract: Maintaining a highly acidic lysosomal pH is central to cellular physiology. Here, we use functional proteomics, single-particle cryo-EM, electrophysiology, and in vivo imaging to unravel a key ...Maintaining a highly acidic lysosomal pH is central to cellular physiology. Here, we use functional proteomics, single-particle cryo-EM, electrophysiology, and in vivo imaging to unravel a key biological function of human lysosome-associated membrane proteins (LAMP-1 and LAMP-2) in regulating lysosomal pH homeostasis. Despite being widely used as a lysosomal marker, the physiological functions of the LAMP proteins have long been overlooked. We show that LAMP-1 and LAMP-2 directly interact with and inhibit the activity of the lysosomal cation channel TMEM175, a key player in lysosomal pH homeostasis implicated in Parkinson's disease. This LAMP inhibition mitigates the proton conduction of TMEM175 and facilitates lysosomal acidification to a lower pH environment crucial for optimal hydrolase activity. Disrupting the LAMP-TMEM175 interaction alkalinizes the lysosomal pH and compromises the lysosomal hydrolytic function. In light of the ever-increasing importance of lysosomes to cellular physiology and diseases, our data have widespread implications for lysosomal biology.
History
DepositionJan 25, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 28, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 19, 2023Group: Database references / Category: citation / citation_author
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.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Aug 2, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Endosomal/lysosomal potassium channel TMEM175
B: Endosomal/lysosomal potassium channel TMEM175
C: Lysosome-associated membrane glycoprotein 1
D: Lysosome-associated membrane glycoprotein 1


Theoretical massNumber of molelcules
Total (without water)201,1914
Polymers201,1914
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


Mass: 55667.219 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TMEM175 / Cell line (production host): Freestyle 293F / Production host: Homo sapiens (human) / References: UniProt: Q9BSA9
#2: Protein Lysosome-associated membrane glycoprotein 1 / LAMP-1 / Lysosome-associated membrane protein 1 / CD107 antigen-like family member A


Mass: 44928.215 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LAMP1 / Cell line (production host): Freestyle 293F / Production host: Homo sapiens (human) / References: UniProt: P11279

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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: TMEM175-LAMP1 full-length / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: Freestyle 293F
Buffer solutionpH: 8
SpecimenConc.: 1.5 mg/ml / Embedding 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 / Nominal defocus max: 2200 nm / Nominal defocus min: 900 nm / C2 aperture diameter: 70 µm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: UCSF ChimeraX / Version: 1.5/v9 / Classification: model building / URL: https://www.rbvi.ucsf.edu/chimerax/ / Os: macOS / Type: package
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 269594 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT

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