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- EMDB-12935: Structure of thermostable human MFSD2A in complex with thermostab... -

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Basic information

Entry
Database: EMDB / ID: EMD-12935
TitleStructure of thermostable human MFSD2A in complex with thermostable human Sync2
Map dataThermostable human MFSD2A transporter in complex with thermostable human SYNC2
Sample
  • Complex: Thermostable human MFSD2A in complex with thermostable human Syncytin-2
    • Protein or peptide: Syncytin-2
    • Protein or peptide: Isoform 2 of Sodium-dependent lysophosphatidylcholine symporter 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


fatty acid transmembrane transporter activity / lysophospholipid translocation / lysophosphatidylcholine flippase activity / regulation of phosphatidylethanolamine metabolic process / regulation of phosphatidylserine metabolic process / oleate transmembrane transporter activity / regulation of phosphatidylcholine metabolic process / regulation of neuron projection arborization / retina morphogenesis in camera-type eye / photoreceptor cell morphogenesis ...fatty acid transmembrane transporter activity / lysophospholipid translocation / lysophosphatidylcholine flippase activity / regulation of phosphatidylethanolamine metabolic process / regulation of phosphatidylserine metabolic process / oleate transmembrane transporter activity / regulation of phosphatidylcholine metabolic process / regulation of neuron projection arborization / retina morphogenesis in camera-type eye / photoreceptor cell morphogenesis / lysophospholipid:sodium symporter activity / lysophospholipid transport / syncytium formation by plasma membrane fusion / syncytium formation / photoreceptor cell outer segment organization / lipid transport across blood-brain barrier / phospholipid transporter activity / very-low-density lipoprotein particle assembly / organic substance transport / negative regulation of fatty acid beta-oxidation / retinal pigment epithelium development / regulation of dendrite development / positive regulation of triglyceride biosynthetic process / phosphatidylcholine biosynthetic process / establishment of blood-brain barrier / myoblast fusion / transcytosis / motor behavior / long-chain fatty acid transmembrane transporter activity / maintenance of blood-brain barrier / Synthesis of PC / plasma membrane => GO:0005886 / transport across blood-brain barrier / regulation of multicellular organism growth / carbohydrate transport / fatty acid transport / long-chain fatty acid transport / energy homeostasis / cellular response to starvation / hippocampus development / brain development / cognition / positive regulation of cell growth / membrane => GO:0016020 / endoplasmic reticulum membrane / plasma membrane
Similarity search - Function
ENV polyprotein (coat polyprotein) / TLV/ENV coat polyprotein / Lactose permease-like / MFS transporter superfamily
Similarity search - Domain/homology
Syncytin-2 / Sodium-dependent lysophosphatidylcholine symporter 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsMartinez-Molledo M / Reyes N
Funding supportEuropean Union, 1 items
OrganizationGrant numberCountry
European Research Council (ERC)771965European Union
CitationJournal: Nat Struct Mol Biol / Year: 2022
Title: Structural insights into the lysophospholipid brain uptake mechanism and its inhibition by syncytin-2.
Authors: Maria Martinez-Molledo / Emmanuel Nji / Nicolas Reyes /
Abstract: Brain development and function require uptake of essential omega-3 fatty acids in the form of lysophosphatidylcholine via major-facilitator superfamily transporter MFSD2A, a potential pharmaceutical ...Brain development and function require uptake of essential omega-3 fatty acids in the form of lysophosphatidylcholine via major-facilitator superfamily transporter MFSD2A, a potential pharmaceutical target to modulate blood-brain barrier (BBB) permeability. MFSD2A is also the receptor of endogenous retroviral envelope syncytin-2 (SYNC2) in human placenta, where it mediates cell-cell fusion and formation of the maternal-fetal interface. Here, we report a cryo-electron microscopy structure of the human MFSD2A-SYNC2 complex that reveals a large hydrophobic cavity in the transporter C-terminal domain to occlude long aliphatic chains. The transporter architecture suggests an alternating-access transport mechanism for lipid substrates in mammalian MFS transporters. SYNC2 establishes an extensive binding interface with MFSD2A, and a SYNC2-soluble fragment acts as a long-sought-after inhibitor of MFSD2A transport. Our work uncovers molecular mechanisms important to brain and placenta development and function, and SYNC2-mediated inhibition of MFSD2A transport suggests strategies to aid delivery of therapeutic macromolecules across the BBB.
History
DepositionMay 12, 2021-
Header (metadata) releaseJun 1, 2022-
Map releaseJun 1, 2022-
UpdateJun 29, 2022-
Current statusJun 29, 2022Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_12935.png

Downloads & links

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Map

FileDownload / File: emd_12935.map.gz / Format: CCP4 / Size: 282.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationThermostable human MFSD2A transporter in complex with thermostable human SYNC2
Voxel sizeX=Y=Z: 0.814 Å
Density
Contour LevelBy AUTHOR: 0.14
Minimum - Maximum-0.60815173 - 1.223691
Average (Standard dev.)0.0010504933 (±0.013845509)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions420420420
Spacing420420420
CellA=B=C: 341.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Additional map for thermostable human MFSD2A transporter in...

Fileemd_12935_additional_1.map
AnnotationAdditional map for thermostable human MFSD2A transporter in complex with thermostable human SYNC2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Thermostable human MFSD2A in complex with thermostable human Sync...

EntireName: Thermostable human MFSD2A in complex with thermostable human Syncytin-2
Components
  • Complex: Thermostable human MFSD2A in complex with thermostable human Syncytin-2
    • Protein or peptide: Syncytin-2
    • Protein or peptide: Isoform 2 of Sodium-dependent lysophosphatidylcholine symporter 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Thermostable human MFSD2A in complex with thermostable human Sync...

SupramoleculeName: Thermostable human MFSD2A in complex with thermostable human Syncytin-2
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK-293F

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Macromolecule #1: Syncytin-2

MacromoleculeName: Syncytin-2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 59.613219 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGLLLLVLIL TPSLAAYRHP DFPLLEKAQQ LLQSTGSPYS TNCWLCTSSS TETPGTAYPA SPREWTSIEA ELHISYRWDP NLKGLMRPA NSLLSTVKQD FPDIRQKPPI FGPIFTNINL MGIAPICVTA KRKNGTNVGT LPSTVCNVTF TVDPNQQTYQ T YTHNQFRH ...String:
MGLLLLVLIL TPSLAAYRHP DFPLLEKAQQ LLQSTGSPYS TNCWLCTSSS TETPGTAYPA SPREWTSIEA ELHISYRWDP NLKGLMRPA NSLLSTVKQD FPDIRQKPPI FGPIFTNINL MGIAPICVTA KRKNGTNVGT LPSTVCNVTF TVDPNQQTYQ T YTHNQFRH QPRFPKPPNI TFPQGTLLDK STRFCQGRPS SCSTRNFWFR PADYNQCLQI SNLSSTAEWV LLDQTRNSLF WE NKTKGAN QSQTPCVQVL AGMTIATSYL GISAVSEFFG TSLTPLFHFH ISTCLKTQGA FYICGQSIHQ CLPSNWTGTC TIG YVTPDI FIAPGNLSLP IPIYGNSPLP RVRRAIHFIP LLAGLGILAG TGTGIAGITK ASLTYSQLSK EIANNIDTMA KALT TMQEQ IDSLAAVVLQ NRRGLDMLTA AQGGICLALD EKCCFWVNQS GKVQDNIRQL LNQASSLRER ATQGWLNWEG TWKWF SWVL PFIGPLVSLL LLLLFGPCLL NLITQFVSSR LQAIKLQTNL SAGRHPRNIQ ESPF

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Macromolecule #2: Isoform 2 of Sodium-dependent lysophosphatidylcholine symporter 1

MacromoleculeName: Isoform 2 of Sodium-dependent lysophosphatidylcholine symporter 1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 58.540805 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAKGEGAESG SAAGLLPTSI LQSTERPAQV KKEPKKKKQQ LSICNKLCYA VGGAPYQVTG CALGFFLQIY LLDVAQVGPF SASIILFVG RAWDAITDPL VGFCISKSSW TRLGRLMPWI IFSTPLAVIA YFLIWFVPDF PHGQTYWYLL FYCLFETLVT C FHVPYSAL ...String:
MAKGEGAESG SAAGLLPTSI LQSTERPAQV KKEPKKKKQQ LSICNKLCYA VGGAPYQVTG CALGFFLQIY LLDVAQVGPF SASIILFVG RAWDAITDPL VGFCISKSSW TRLGRLMPWI IFSTPLAVIA YFLIWFVPDF PHGQTYWYLL FYCLFETLVT C FHVPYSAL TMFISTEQSE RDSATAYRMT VEVLGTVLGT AIQGQIVGQA DTPCFQDLNS STVASQSANH THGTTSHRET QN AYLLAAG VIASIYVICA VILTLGVREQ REPYEAQQSE PMSFFRGLRL VMSHGPYIKL IAGFLFTSLA FMLVEGNFAL FCT YTLGFR NEFQNLLLAI MLSATLTIPI WQWFLTRFGK KTAVYVGISS AVPFLILVAL MESNLIVTYV VAVAAGISVA AAFL LPWSM LPDVIDDFHL KQPHSHGTEP IFFSFYVFFT KFASGVSLGI STLSLDFAGY QTRGCSQPER VKFTLKMLVT MAPIV LILL GLLLFKLYPI DEERRRQNKK ALQALRDEAS SSGCSETDST ELASIL

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

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

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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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

Concentration1.2 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
20.0 mMHEPES4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
150.0 mMNaClSodium chloridesodium chloride
0.0084 %GDNglyco-diosgenin
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Pretreatment - Type: GLOW DISCHARGE / Details: 2 mA
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.5 µm
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 47.1 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1461938
CTF correctionSoftware - Name: cryoSPARC (ver. 2.12.4) / Software - details: Patch CTF estimation
Initial angle assignmentType: NOT APPLICABLE
Final 3D classificationNumber classes: 1 / Software - Name: cryoSPARC (ver. 2.12.4)
Final angle assignmentType: NOT APPLICABLE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 94703

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-7oix:
Structure of thermostable human MFSD2A in complex with thermostable human Sync2

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