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- EMDB-18336: Cryo-EM structure of the inward-facing FLVCR2 -

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Basic information

Entry
Database: EMDB / ID: EMD-18336
TitleCryo-EM structure of the inward-facing FLVCR2
Map data
Sample
  • Complex: FLVCR2 monomer
    • Protein or peptide: Heme transporter FLVCR2
KeywordsMFS / choline transport / human transporter / MEMBRANE PROTEIN
Function / homology
Function and homology information


heme export / ethanolamine transmembrane transporter activity / choline transmembrane transporter activity / heme transmembrane transporter activity / choline transport / transport across blood-brain barrier / mitochondrial membrane / heme binding / endoplasmic reticulum membrane / membrane / plasma membrane
Similarity search - Function
: / Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Choline/ethanolamine transporter FLVCR2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsWeng T-H / Wu D / Safarian S
Funding support Germany, 1 items
OrganizationGrant numberCountry
Max Planck Society Germany
CitationJournal: Nature / Year: 2024
Title: Molecular mechanism of choline and ethanolamine transport in humans.
Authors: Keiken Ri / Tsai-Hsuan Weng / Ainara Claveras Cabezudo / Wiebke Jösting / Yu Zhang / Andre Bazzone / Nancy C P Leong / Sonja Welsch / Raymond T Doty / Gonca Gursu / Tiffany Jia Ying Lim / ...Authors: Keiken Ri / Tsai-Hsuan Weng / Ainara Claveras Cabezudo / Wiebke Jösting / Yu Zhang / Andre Bazzone / Nancy C P Leong / Sonja Welsch / Raymond T Doty / Gonca Gursu / Tiffany Jia Ying Lim / Sarah Luise Schmidt / Janis L Abkowitz / Gerhard Hummer / Di Wu / Long N Nguyen / Schara Safarian /
Abstract: Human feline leukaemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and FLVCR2) are members of the major facilitator superfamily. Their dysfunction is linked to several clinical ...Human feline leukaemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and FLVCR2) are members of the major facilitator superfamily. Their dysfunction is linked to several clinical disorders, including PCARP, HSAN and Fowler syndrome. Earlier studies concluded that FLVCR1 may function as a haem exporter, whereas FLVCR2 was suggested to act as a haem importer, yet conclusive biochemical and detailed molecular evidence remained elusive for the function of both transporters. Here, we show that FLVCR1 and FLVCR2 facilitate the transport of choline and ethanolamine across the plasma membrane, using a concentration-driven substrate translocation process. Through structural and computational analyses, we have identified distinct conformational states of FLVCRs and unravelled the coordination chemistry underlying their substrate interactions. Fully conserved tryptophan and tyrosine residues form the binding pocket of both transporters and confer selectivity for choline and ethanolamine through cation-π interactions. Our findings clarify the mechanisms of choline and ethanolamine transport by FLVCR1 and FLVCR2, enhance our comprehension of disease-associated mutations that interfere with these vital processes and shed light on the conformational dynamics of these major facilitator superfamily proteins during the transport cycle.
History
DepositionAug 28, 2023-
Header (metadata) releaseApr 17, 2024-
Map releaseApr 17, 2024-
UpdateJun 19, 2024-
Current statusJun 19, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18336.png

Downloads & links

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Map

FileDownload / File: emd_18336.map.gz / Format: CCP4 / Size: 14.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.15 Å/pix.
x 156 pix.
= 178.776 Å		1.15 Å/pix.
x 156 pix.
= 178.776 Å		1.15 Å/pix.
x 156 pix.
= 178.776 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.146 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.12
Minimum - Maximum-4.004377 - 5.884735
Average (Standard dev.)0.0043503726 (±0.19375153)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions156156156
Spacing156156156
CellA=B=C: 178.776 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_18336_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_18336_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : FLVCR2 monomer

EntireName: FLVCR2 monomer
Components
  • Complex: FLVCR2 monomer
    • Protein or peptide: Heme transporter FLVCR2

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Supramolecule #1: FLVCR2 monomer

SupramoleculeName: FLVCR2 monomer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 58 KDa

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Macromolecule #1: Heme transporter FLVCR2

MacromoleculeName: Heme transporter FLVCR2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 58.277094 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MVNEGPNQEE SDDTPVPESA LQADPSVSVH PSVSVHPSVS INPSVSVHPS SSAHPSALAQ PSGLAHPSSS GPEDLSVIKV SRRRWAVVL VFSCYSMCNS FQWIQYGSIN NIFMHFYGVS AFAIDWLSMC YMLTYIPLLL PVAWLLEKFG LRTIALTGSA L NCLGAWVK ...String:
MVNEGPNQEE SDDTPVPESA LQADPSVSVH PSVSVHPSVS INPSVSVHPS SSAHPSALAQ PSGLAHPSSS GPEDLSVIKV SRRRWAVVL VFSCYSMCNS FQWIQYGSIN NIFMHFYGVS AFAIDWLSMC YMLTYIPLLL PVAWLLEKFG LRTIALTGSA L NCLGAWVK LGSLKPHLFP VTVVGQLICS VAQVFILGMP SRIASVWFGA NEVSTACSVA VFGNQLGIAI GFLVPPVLVP NI EDRDELA YHISIMFYII GGVATLLLIL VIIVFKEKPK YPPSRAQSLS YALTSPDASY LGSIARLFKN LNFVLLVITY GLN AGAFYA LSTLLNRMVI WHYPGEEVNA GRIGLTIVIA GMLGAVISGI WLDRSKTYKE TTLVVYIMTL VGMVVYTFTL NLGH LWVVF ITAGTMGFFM TGYLPLGFEF AVELTYPESE GISSGLLNIS AQVFGIIFTI SQGQIIDNYG TKPGNIFLCV FLTLG AALT AFIKADLRRQ KANKETLENK LQEEEEESNT SKVPTAVSED HLDYKDDDDK

UniProtKB: Choline/ethanolamine transporter FLVCR2

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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: 7.4
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 90 sec.
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 80.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.1 µm / Nominal defocus min: 1.1 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 3497517
Startup modelType of model: OTHER / Details: Ab initio reconstruction
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 50167
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

3-f1


Chain - Chain ID: A / Chain - Source name: AlphaFold / Chain - Initial model type: in silico model
Output model

PDB-8qcx:
Cryo-EM structure of the inward-facing FLVCR2

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