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- PDB-8qcs: Cryo-EM structure of the inward-facing FLVCR1 -

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Basic information

Entry
Database: PDB / ID: 8qcs
TitleCryo-EM structure of the inward-facing FLVCR1
ComponentsHeme transporter FLVCR1
KeywordsMEMBRANE PROTEIN / MFS / choline / human transporter
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 / regulation of organ growth / head morphogenesis ...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 / regulation of organ growth / head morphogenesis / 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 / in utero embryonic development / intracellular iron ion homeostasis / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsWeng, T.-H. / Wu, D. / Safarian, S.
Funding support Germany, 1items
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, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 17, 2024Provider: repository / Type: Initial release
Revision 1.1May 22, 2024Group: Database references / Category: citation
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.title / _citation.year
Revision 1.2Jun 5, 2024Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Jun 19, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Heme transporter FLVCR1


Theoretical massNumber of molelcules
Total (without water)60,8961
Polymers60,8961
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Heme transporter FLVCR1 / Feline leukemia virus subgroup C receptor-related protein 1 / Feline leukemia virus subgroup C ...Feline leukemia virus subgroup C receptor-related protein 1 / Feline leukemia virus subgroup C receptor / hFLVCR


Mass: 60896.316 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FLVCR1, FLVCR / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q9Y5Y0
Has ligand of interestY

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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: FLVCR1 monomer / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.06 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293
Buffer solutionpH: 7.4
SpecimenConc.: 1.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
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: 2100 nm / Nominal defocus min: 1100 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDName
1RELION
2ISOLDE
3Coot
4cryoSPARC
5PHENIX
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 3247307
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 56664 / Algorithm: BACK PROJECTION / Symmetry type: POINT
Atomic model buildingAccession code: AF-Q9Y5Y0-F1 / Source name: AlphaFold / Type: in silico model
RefinementHighest resolution: 2.9 Å

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