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- EMDB-29553: Human TMEM175-LAMP1 full-length complex -

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Basic information

Entry
Database: EMDB / ID: EMD-29553
TitleHuman TMEM175-LAMP1 full-length complex
Map dataTMEM175-LAMP1 full-length complex
Sample
  • Complex: TMEM175-LAMP1 full-length
    • Protein or peptide: Endosomal/lysosomal potassium channel TMEM175
    • Protein or peptide: Lysosome-associated membrane glycoprotein 1
KeywordsComplex / MEMBRANE PROTEIN
Function / homology
Function and homology information


regulation of organelle transport along microtubule / granzyme-mediated programmed cell death signaling pathway / lysosomal lumen pH elevation / phagolysosome membrane / cytolytic granule membrane / phagosome-lysosome fusion / positive regulation of natural killer cell degranulation / establishment of protein localization to organelle / regulation of lysosomal lumen pH / Golgi to lysosome transport ...regulation of organelle transport along microtubule / granzyme-mediated programmed cell death signaling pathway / lysosomal lumen pH elevation / phagolysosome membrane / cytolytic granule membrane / phagosome-lysosome fusion / positive regulation of natural killer cell degranulation / establishment of protein localization to organelle / regulation of lysosomal lumen pH / Golgi to lysosome transport / potassium ion leak channel activity / lysosomal lumen acidification / proton channel activity / arachidonic acid binding / autolysosome / azurophil granule membrane / ion channel inhibitor activity / positive regulation of natural killer cell mediated cytotoxicity / autophagosome membrane / potassium channel activity / ficolin-1-rich granule membrane / potassium ion transmembrane transport / proton transmembrane transport / multivesicular body / sarcolemma / neuron cellular homeostasis / melanosome / synaptic vesicle / late endosome / virus receptor activity / late endosome membrane / lysosome / protein stabilization / endosome membrane / endosome / lysosomal membrane / protein domain specific binding / 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 2, transmembrane segment / Lysosome-associated membrane glycoprotein, conserved site / Lysosome-associated membrane glycoproteins duplicated domain signature. / LAMP glycoproteins transmembrane and cytoplasmic domain signature. / Lysosome-associated membrane glycoprotein / Lysosome-associated membrane glycoprotein (Lamp) / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsZhang JY / Zeng WZ / Han Y / Jiang YX
Funding support United States, 1 items
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, 2023-
Header (metadata) releaseJun 28, 2023-
Map releaseJun 28, 2023-
UpdateAug 2, 2023-
Current statusAug 2, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29553.png

Downloads & links

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Map

FileDownload / File: emd_29553.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationTMEM175-LAMP1 full-length complex
Voxel sizeX=Y=Z: 0.83 Å
Density
Contour LevelBy AUTHOR: 0.03
Minimum - Maximum-0.09005417 - 0.15666035
Average (Standard dev.)0.00027087753 (±0.0037111812)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 239.04 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_29553_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_29553_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : TMEM175-LAMP1 full-length

EntireName: TMEM175-LAMP1 full-length
Components
  • Complex: TMEM175-LAMP1 full-length
    • Protein or peptide: Endosomal/lysosomal potassium channel TMEM175
    • Protein or peptide: Lysosome-associated membrane glycoprotein 1

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Supramolecule #1: TMEM175-LAMP1 full-length

SupramoleculeName: TMEM175-LAMP1 full-length / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Endosomal/lysosomal potassium channel TMEM175

MacromoleculeName: Endosomal/lysosomal potassium channel TMEM175 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.667219 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSQPRTPEQA LDTPGDCPPG RRDEDAGEGI QCSQRMLSFS DALLSIIATV MILPVTHTEI SPEQQFDRSV QRLLATRIAV YLMTFLIVT VAWAAHTRLF QVVGKTDDTL ALLNLACMMT ITFLPYTFSL MVTFPDVPLG IFLFCVCVIA IGVVQALIVG Y AFHFPHLL ...String:
MSQPRTPEQA LDTPGDCPPG RRDEDAGEGI QCSQRMLSFS DALLSIIATV MILPVTHTEI SPEQQFDRSV QRLLATRIAV YLMTFLIVT VAWAAHTRLF QVVGKTDDTL ALLNLACMMT ITFLPYTFSL MVTFPDVPLG IFLFCVCVIA IGVVQALIVG Y AFHFPHLL SPQIQRSAHR ALYRRHVLGI VLQGPALCFA AAIFSLFFVP LSYLLMVTVI LLPYVSKVTG WCRDRLLGHR EP SAHPVEV FSFDLHEPLS KERVEAFSDG VYAIVATLLI LDICEDNVPD PKDVKERFSG SLVAALSATG PRFLAYFGSF ATV GLLWFA HHSLFLHVRK ATRAMGLLNT LSLAFVGGLP LAYQQTSAFA RQPRDELERV RVSCTIIFLA SIFQLAMWTT ALLH QAETL QPSVWFGGRE HVLMFAKLAL YPCASLLAFA STCLLSRFSV GIFHLMQIAV PCAFLLLRLL VGLALATLRV LRGLA RPEH PPPAPTGQDD PQSQLLPAPC

UniProtKB: Endosomal/lysosomal proton channel TMEM175

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Macromolecule #2: Lysosome-associated membrane glycoprotein 1

MacromoleculeName: Lysosome-associated membrane glycoprotein 1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44.928215 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAAPGSARRP LLLLLLLLLL GLMHCASAAM FMVKNGNGTA CIMANFSAAF SVNYDTKSGP KNMTFDLPSD ATVVLNRSSC GKENTSDPS LVIAFGRGHT LTLNFTRNAT RYSVQLMSFV YNLSDTHLFP NASSKEIKTV ESITDIRADI DKKYRCVSGT Q VHMNNVTV ...String:
MAAPGSARRP LLLLLLLLLL GLMHCASAAM FMVKNGNGTA CIMANFSAAF SVNYDTKSGP KNMTFDLPSD ATVVLNRSSC GKENTSDPS LVIAFGRGHT LTLNFTRNAT RYSVQLMSFV YNLSDTHLFP NASSKEIKTV ESITDIRADI DKKYRCVSGT Q VHMNNVTV TLHDATIQAY LSNSSFSRGE TRCEQDRPSP TTAPPAPPSP SPSPVPKSPS VDKYNVSGTN GTCLLASMGL QL NLTYERK DNTTVTRLLN INPNKTSASG SCGAHLVTLE LHSEGTTVLL FQFGMNASSS RFFLQGIQLN TILPDARDPA FKA ANGSLR ALQATVGNSY KCNAEEHVRV TKAFSVNIFK VWVQAFKVEG GQFGSVEECL LDENSMLIPI AVGGALAGLV LIVL IAYLV GRKRSHAGYQ TI

UniProtKB: Lysosome-associated membrane glycoprotein 1

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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

Concentration1.5 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.9 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

21603

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 269594
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: FLEXIBLE FIT
Output model

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

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