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- EMDB-18335: Cryo-EM structure of the inward-facing choline-bound FLVCR1 -

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Basic information

Entry
Database: EMDB / ID: EMD-18335
TitleCryo-EM structure of the inward-facing choline-bound FLVCR1
Map data
Sample
  • Complex: choline-bound FLVCR1 monomer
    • Protein or peptide: Heme transporter FLVCR1
  • Ligand: CHOLINE ION
KeywordsMFS / choline transport / human transporter / MEMBRANE PROTEIN
Function / homology
Function and homology information


heme export / ethanolamine transmembrane transporter activity / choline transmembrane transporter activity / heme transport / heme transmembrane transporter activity / embryonic skeletal system morphogenesis / choline transport / phospholipid biosynthetic process / head morphogenesis / regulation of organ growth ...heme export / ethanolamine transmembrane transporter activity / choline transmembrane transporter activity / heme transport / heme transmembrane transporter activity / embryonic skeletal system morphogenesis / choline transport / phospholipid biosynthetic process / head morphogenesis / regulation of organ growth / Heme biosynthesis / heme biosynthetic process / embryonic digit morphogenesis / mitochondrial transport / blood vessel development / erythrocyte maturation / spleen development / erythrocyte differentiation / Iron uptake and transport / multicellular organism growth / intracellular iron ion homeostasis / in utero embryonic development / mitochondrial inner membrane / heme binding / mitochondrion / 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 FLVCR1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.6 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_18335.png

Downloads & links

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Map

FileDownload / File: emd_18335.map.gz / Format: CCP4 / Size: 11.4 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 144 pix.
= 165.024 Å		1.15 Å/pix.
x 144 pix.
= 165.024 Å		1.15 Å/pix.
x 144 pix.
= 165.024 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: 0.045
Minimum - Maximum-0.11007669 - 0.21278557
Average (Standard dev.)0.00018886823 (±0.0051790983)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions144144144
Spacing144144144
CellA=B=C: 165.024 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_18335_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_18335_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 : choline-bound FLVCR1 monomer

EntireName: choline-bound FLVCR1 monomer
Components
  • Complex: choline-bound FLVCR1 monomer
    • Protein or peptide: Heme transporter FLVCR1
  • Ligand: CHOLINE ION

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Supramolecule #1: choline-bound FLVCR1 monomer

SupramoleculeName: choline-bound FLVCR1 monomer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 60 KDa

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Macromolecule #1: Heme transporter FLVCR1

MacromoleculeName: Heme transporter FLVCR1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 60.896316 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MARPDDEEGA AVAPGHPLAK GYLPLPRGAP VGKESVELQN GPKAGTFPVN GAPRDSLAAA SGVLGGPQTP LAPEEETQAR LLPAGAGAE TPGAESSPLP LTALSPRRFV VLLIFSLYSL VNAFQWIQYS IISNVFEGFY GVTLLHIDWL SMVYMLAYVP L IFPATWLL ...String:
MARPDDEEGA AVAPGHPLAK GYLPLPRGAP VGKESVELQN GPKAGTFPVN GAPRDSLAAA SGVLGGPQTP LAPEEETQAR LLPAGAGAE TPGAESSPLP LTALSPRRFV VLLIFSLYSL VNAFQWIQYS IISNVFEGFY GVTLLHIDWL SMVYMLAYVP L IFPATWLL DTRGLRLTAL LGSGLNCLGA WIKCGSVQQH LFWVTMLGQC LCSVAQVFIL GLPSRIASVW FGPKEVSTAC AT AVLGNQL GTAVGFLLPP VLVPNTQNDT NLLACNISTM FYGTSAVATL LFILTAIAFK EKPRYPPSQA QAALQDSPPE EYS YKKSIR NLFKNIPFVL LLITYGIMTG AFYSVSTLLN QMILTYYEGE EVNAGRIGLT LVVAGMVGSI LCGLWLDYTK TYKQ TTLIV YILSFIGMVI FTFTLDLRYI IIVFVTGGVL GFFMTGYLPL GFEFAVEITY PESEGTSSGL LNASAQIFGI LFTLA QGKL TSDYGPKAGN IFLCVWMFIG IILTALIKSD LRRHNINIGI TNVDVKAIPA DSPTDQEPKT VMLSKQSESA IDYKDD DDK

UniProtKB: Choline/ethanolamine transporter FLVCR1

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Macromolecule #2: CHOLINE ION

MacromoleculeName: CHOLINE ION / type: ligand / ID: 2 / Number of copies: 1 / Formula: CHT
Molecular weightTheoretical: 104.171 Da
Chemical component information

ChemComp-CHT:
CHOLINE ION

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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: 55.0 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: 3251081
Startup modelType of model: OTHER / Details: Ab initio reconstruction
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 25873
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

0-f1


Chain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL
Output model

PDB-8qct:
Cryo-EM structure of the inward-facing choline-bound FLVCR1

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