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- EMDB-19006: Lysosomal peptide transporter -

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Open data


ID or keywords:

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Basic information

Entry
Database: EMDB / ID: EMD-19006
TitleLysosomal peptide transporter
Map data
Sample
  • Complex: GLMP-MFSD1
    • Protein or peptide: Major facilitator superfamily domain-containing protein 1
    • Protein or peptide: Glycosylated lysosomal membrane protein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsMFS transporter / MFSD family / nutrition transporter / lysosomal transporter / outward open / MEMBRANE PROTEIN
Function / homology
Function and homology information


dipeptide transmembrane transport from lysosomal lumen to cytosol / dipeptide uniporter activity / protein localization to lysosome / lysosome / protein stabilization / lysosomal membrane / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / membrane / nucleus / cytosol
Similarity search - Function
: / Lysosomal transcription factor, NCU-G1 / Lysosomal transcription factor, NCU-G1 / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Lysosomal dipeptide transporter MFSD1 / Glycosylated lysosomal membrane protein
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.08 Å
AuthorsJungnickel KEJ / Loew C
Funding support Germany, 1 items
OrganizationGrant numberCountry
Other government05K18YEA Germany
CitationJournal: Nat Cell Biol / Year: 2024
Title: MFSD1 with its accessory subunit GLMP functions as a general dipeptide uniporter in lysosomes.
Authors: Katharina Esther Julia Jungnickel / Océane Guelle / Miharu Iguchi / Wentao Dong / Vadim Kotov / Florian Gabriel / Cécile Debacker / Julien Dairou / Isabelle McCort-Tranchepain / Nouf N ...Authors: Katharina Esther Julia Jungnickel / Océane Guelle / Miharu Iguchi / Wentao Dong / Vadim Kotov / Florian Gabriel / Cécile Debacker / Julien Dairou / Isabelle McCort-Tranchepain / Nouf N Laqtom / Sze Ham Chan / Akika Ejima / Kenji Sato / David Massa López / Paul Saftig / Ahmad Reza Mehdipour / Monther Abu-Remaileh / Bruno Gasnier / Christian Löw / Markus Damme /
Abstract: The lysosomal degradation of macromolecules produces diverse small metabolites exported by specific transporters for reuse in biosynthetic pathways. Here we deorphanized the major facilitator ...The lysosomal degradation of macromolecules produces diverse small metabolites exported by specific transporters for reuse in biosynthetic pathways. Here we deorphanized the major facilitator superfamily domain containing 1 (MFSD1) protein, which forms a tight complex with the glycosylated lysosomal membrane protein (GLMP) in the lysosomal membrane. Untargeted metabolomics analysis of MFSD1-deficient mouse lysosomes revealed an increase in cationic dipeptides. Purified MFSD1 selectively bound diverse dipeptides, while electrophysiological, isotope tracer and fluorescence-based studies in Xenopus oocytes and proteoliposomes showed that MFSD1-GLMP acts as a uniporter for cationic, neutral and anionic dipeptides. Cryoelectron microscopy structure of the dipeptide-bound MFSD1-GLMP complex in outward-open conformation characterized the heterodimer interface and, in combination with molecular dynamics simulations, provided a structural basis for its selectivity towards diverse dipeptides. Together, our data identify MFSD1 as a general lysosomal dipeptide uniporter, providing an alternative route to recycle lysosomal proteolysis products when lysosomal amino acid exporters are overloaded.
History
DepositionNov 29, 2023-
Header (metadata) releaseMay 1, 2024-
Map releaseMay 1, 2024-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_19006.png

Downloads & links

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Map

FileDownload / File: emd_19006.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.)
1.1 Å/pix.
x 300 pix.
= 330. Å		1.1 Å/pix.
x 300 pix.
= 330. Å		1.1 Å/pix.
x 300 pix.
= 330. Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.443
Minimum - Maximum-2.9615512 - 4.0634503
Average (Standard dev.)0.0010480474 (±0.053601544)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 330.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_19006_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_19006_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : GLMP-MFSD1

EntireName: GLMP-MFSD1
Components
  • Complex: GLMP-MFSD1
    • Protein or peptide: Major facilitator superfamily domain-containing protein 1
    • Protein or peptide: Glycosylated lysosomal membrane protein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: GLMP-MFSD1

SupramoleculeName: GLMP-MFSD1 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Major facilitator superfamily domain-containing protein 1

MacromoleculeName: Major facilitator superfamily domain-containing protein 1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 55.765551 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MEDEDGEDRA LLGGRREADS AVHGAPRALS ALCDPSRLAH RLVVLSLMCF LGFGSYFCYD NPAALQTQVK RDMQVNTTKF MLLYAWYSW PNVVLCFLGG FLIDRIFGIR WGTVIFSCFV CIGQVIFALG GIFNAFWLME LGRFVFGIGG ESLAVAQNTY A VSWFKGKE ...String:
MEDEDGEDRA LLGGRREADS AVHGAPRALS ALCDPSRLAH RLVVLSLMCF LGFGSYFCYD NPAALQTQVK RDMQVNTTKF MLLYAWYSW PNVVLCFLGG FLIDRIFGIR WGTVIFSCFV CIGQVIFALG GIFNAFWLME LGRFVFGIGG ESLAVAQNTY A VSWFKGKE LNLVFGLQLS MARIGSTVNM NLMGWLYGKI EALLGSAGHM TLGVTLMIGC ITCIFSLICA LALAYLDRRA EK ILHKEQG KTGEVIKLRD IKDFSLPLIL VFVICVCYYV AVFPFIGLGK VFFMEKFRFS SQSASAINSI VYIISAPMSP LFG LLVDKT GKNIIWVLYA VAATLVSHMM LAFTFWNPWI AMCLLGFSYS LLACALWPMV AFIVPEHQLG TAYGFMQSIQ NLGL AVIAI LAGMILDSKG YLLLEVFFIA CVSLSLLAVV CLYLVNRAQG GNLNYSAKQR ERMKLSHPEI IILEVLFQGP SSGWS HPQF EKGGGSGGGS GGSAWSHPQF EK

UniProtKB: Lysosomal dipeptide transporter MFSD1

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Macromolecule #2: Glycosylated lysosomal membrane protein

MacromoleculeName: Glycosylated lysosomal membrane protein / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 43.102711 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MFRCWGPHWG WVPCAPTPWL LLSLLVCSAP FGLQGEETRQ VSMEVISGWP NPQNLLHIRA VGSNSTLHYV WSSLGPPAVV LVATNTTQS VLSVNWSLLL SPDPAGALMV LPKSSIQFSS ALVFTRLLEF DSTNASEGAQ PPGKPYPPYS LAKFSWNNIT N SLDLANLS ...String:
MFRCWGPHWG WVPCAPTPWL LLSLLVCSAP FGLQGEETRQ VSMEVISGWP NPQNLLHIRA VGSNSTLHYV WSSLGPPAVV LVATNTTQS VLSVNWSLLL SPDPAGALMV LPKSSIQFSS ALVFTRLLEF DSTNASEGAQ PPGKPYPPYS LAKFSWNNIT N SLDLANLS ADFQGRPVDD PTGAFANGSL TFKVQAFSRS GRPAQPPRLL HTADVCQLEV ALVGASPRGN HSLFGLEVAT LG QGPDCPS VNERNSIDDE YAPAVFQLNQ LLWGSSPSGF MQWRPVAFSE EERARESALP CQASTLHSTL ASSLPHSPIV QAF FGSQNN FCAFNLTFGA PTGPGYWDQY YLCWSMLLGM GFPPVDIFSP LVLGIMAVAL GAPGLMFLGG GLFLLGSAGS AAGS GEF

UniProtKB: Glycosylated lysosomal membrane protein

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

Concentration3.33 mg/mL
BufferpH: 7.5
Component:
ConcentrationNameFormula
20.0 mMHis-Ala
150.0 mMsodium chlorideNaCl
0.015 %DDM
0.0015 %CHS
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 120 sec.
VitrificationCryogen name: PROPANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 3193 / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 81000
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.08 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 400191
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationSoftware - Name: cryoSPARC

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-8r8q:
Lysosomal peptide transporter

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