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- PDB-8ubw: Choline-bound FLVCR1 -

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Basic information

Entry
Database: PDB / ID: 8ubw
TitleCholine-bound FLVCR1
ComponentsHeme transporter FLVCR1
KeywordsTRANSPORT PROTEIN / Choline / ethanolamine / membrane transport
Function / homology
Function and homology information


heme export / heme transport / heme transmembrane transporter activity / embryonic skeletal system morphogenesis / head morphogenesis / regulation of organ growth / Heme biosynthesis / heme biosynthetic process / embryonic digit morphogenesis / mitochondrial transport ...heme export / heme transport / heme transmembrane transporter activity / embryonic skeletal system morphogenesis / 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 / mitochondrial inner membrane / in utero embryonic development / intracellular iron ion homeostasis / 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 ION / CHOLESTEROL HEMISUCCINATE / Heme transporter FLVCR1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.59 Å
AuthorsHite, R.K. / Son, Y.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nature / Year: 2024
Title: Structural basis of lipid head group entry to the Kennedy pathway by FLVCR1.
Authors: Yeeun Son / Timothy C Kenny / Artem Khan / Kıvanç Birsoy / Richard K Hite /
Abstract: Phosphatidylcholine and phosphatidylethanolamine, the two most abundant phospholipids in mammalian cells, are synthesized de novo by the Kennedy pathway from choline and ethanolamine, respectively. ...Phosphatidylcholine and phosphatidylethanolamine, the two most abundant phospholipids in mammalian cells, are synthesized de novo by the Kennedy pathway from choline and ethanolamine, respectively. Despite the essential roles of these lipids, the mechanisms that enable the cellular uptake of choline and ethanolamine remain unknown. Here we show that the protein encoded by FLVCR1, whose mutation leads to the neurodegenerative syndrome posterior column ataxia and retinitis pigmentosa, transports extracellular choline and ethanolamine into cells for phosphorylation by downstream kinases to initiate the Kennedy pathway. Structures of FLVCR1 in the presence of choline and ethanolamine reveal that both metabolites bind to a common binding site comprising aromatic and polar residues. Despite binding to a common site, FLVCR1 interacts in different ways with the larger quaternary amine of choline in and with the primary amine of ethanolamine. Structure-guided mutagenesis identified residues that are crucial for the transport of ethanolamine, but dispensable for choline transport, enabling functional separation of the entry points into the two branches of the Kennedy pathway. Altogether, these studies reveal how FLVCR1 is a high-affinity metabolite transporter that serves as the common origin for phospholipid biosynthesis by two branches of the Kennedy pathway.
History
DepositionSep 25, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 27, 2024Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Database references / Category: citation / citation_author
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.year
Revision 1.2May 15, 2024Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Heme transporter FLVCR1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,4645
Polymers59,8991
Non-polymers1,5644
Water68538
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Heme transporter FLVCR1


Mass: 59899.352 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FLVCR1 / Production host: Homo sapiens (human) / References: UniProt: Q9Y5Y0
#2: Chemical ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C31H50O4
#3: Chemical ChemComp-CHT / CHOLINE ION / Choline


Mass: 104.171 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H14NO / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 38 / Source method: isolated from a natural source / Formula: H2O
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: Human FLVCR1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
Details: 0.01 % LMNG, 0.001 % CHS, 20 mM HEPES (pHed with KOH, pH 7.5), 150 mM KCl, 1 mM choline chloride
Buffer component
IDConc.NameFormulaBuffer-ID
10.01 %Lauryl Maltose Neopentyl Glycol1
20.001 %Cholesterol hemi succinate1
320 mMHEPES1
4150 mMKCl1
51 mMCholine chloride1
SpecimenConc.: 6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 297 K

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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 FIELDBright-field microscopy / Nominal defocus max: 1500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 53.98 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)
EM imaging opticsEnergyfilter name: TFS Selectris X

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Processing

EM software
IDNameCategory
2Leginonimage acquisition
10cryoSPARCfinal Euler assignment
11cryoSPARCclassification
12cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2712047
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.59 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 282773 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Atomic model buildingProtocol: BACKBONE TRACE / Space: REAL / Target criteria: FSC 0.5
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0023455
ELECTRON MICROSCOPYf_angle_d0.4384728
ELECTRON MICROSCOPYf_dihedral_angle_d4.386488
ELECTRON MICROSCOPYf_chiral_restr0.033569
ELECTRON MICROSCOPYf_plane_restr0.003557

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