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- EMDB-24252: Cryo-EM structure of MFSD2A -

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Basic information

Entry
Database: EMDB / ID: EMD-24252
TitleCryo-EM structure of MFSD2A
Map data
Sample
  • Complex: membrane protein complexBiological membrane
    • Protein or peptide: Sodium-dependent lysophosphatidylcholine symporter 1
Function / homology
Function and homology information


Synthesis of PC / 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 / fatty acid transmembrane transporter activity / photoreceptor cell morphogenesis ...Synthesis of PC / 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 / fatty acid transmembrane transporter activity / photoreceptor cell morphogenesis / lysophospholipid translocation / lysophospholipid:sodium symporter activity / lysophospholipid transport / photoreceptor cell outer segment organization / lipid transport across blood-brain barrier / very-low-density lipoprotein particle assembly / negative regulation of fatty acid beta-oxidation / retinal pigment epithelium development / regulation of dendrite development / : / positive regulation of triglyceride biosynthetic process / establishment of blood-brain barrier / symporter activity / transcytosis / motor behavior / long-chain fatty acid transmembrane transporter activity / maintenance of blood-brain barrier / plasma membrane => GO:0005886 / carbohydrate transport / regulation of multicellular organism growth / fatty acid transport / long-chain fatty acid transport / energy homeostasis / cellular response to starvation / hippocampus development / brain development / cognition / positive regulation of cell growth / endoplasmic reticulum membrane / plasma membrane
Similarity search - Function
Lactose permease-like / MFS transporter superfamily
Similarity search - Domain/homology
Sodium-dependent lysophosphatidylcholine symporter 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsZhang J / Feng L
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA) United States
CitationJournal: Nature / Year: 2021
Title: Structure and mechanism of blood-brain-barrier lipid transporter MFSD2A.
Authors: Chase A P Wood / Jinru Zhang / Deniz Aydin / Yan Xu / Benjamin J Andreone / Urs H Langen / Ron O Dror / Chenghua Gu / Liang Feng /
Abstract: MFSD2A is a sodium-dependent lysophosphatidylcholine symporter that is responsible for the uptake of docosahexaenoic acid into the brain, which is crucial for the development and performance of the ...MFSD2A is a sodium-dependent lysophosphatidylcholine symporter that is responsible for the uptake of docosahexaenoic acid into the brain, which is crucial for the development and performance of the brain. Mutations that affect MFSD2A cause microcephaly syndromes. The ability of MFSD2A to transport lipid is also a key mechanism that underlies its function as an inhibitor of transcytosis to regulate the blood-brain barrier. Thus, MFSD2A represents an attractive target for modulating the permeability of the blood-brain barrier for drug delivery. Here we report the cryo-electron microscopy structure of mouse MFSD2A. Our structure defines the architecture of this important transporter, reveals its unique extracellular domain and uncovers its substrate-binding cavity. The structure-together with our functional studies and molecular dynamics simulations-identifies a conserved sodium-binding site, reveals a potential lipid entry pathway and helps to rationalize MFSD2A mutations that underlie microcephaly syndromes. These results shed light on the critical lipid transport function of MFSD2A and provide a framework to aid in the design of specific modulators for therapeutic purposes.
History
DepositionJun 17, 2021-
Header (metadata) releaseAug 4, 2021-
Map releaseAug 4, 2021-
UpdateSep 1, 2021-
Current statusSep 1, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 7.45
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 7.45
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7n98
  • Surface level: 7.45
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7n98
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_24252.png

Downloads & links

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Map

FileDownload / File: emd_24252.map.gz / Format: CCP4 / Size: 47.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.86 Å
Density
Contour LevelBy AUTHOR: 7.45 / Movie #1: 7.45
Minimum - Maximum-20.16904 - 30.35422
Average (Standard dev.)4.674832e-12 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions232232232
Spacing232232232
CellA=B=C: 199.52 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.860.860.86
M x/y/z232232232
origin x/y/z0.0000.0000.000
length x/y/z199.520199.520199.520
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ232232232
MAP C/R/S321
start NC/NR/NS000
NC/NR/NS232232232
D min/max/mean-20.16930.3540.000

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Supplemental data

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Half map: #2

Fileemd_24252_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_24252_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : membrane protein complex

EntireName: membrane protein complexBiological membrane
Components
  • Complex: membrane protein complexBiological membrane
    • Protein or peptide: Sodium-dependent lysophosphatidylcholine symporter 1

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Supramolecule #1: membrane protein complex

SupramoleculeName: membrane protein complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293

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Macromolecule #1: Sodium-dependent lysophosphatidylcholine symporter 1

MacromoleculeName: Sodium-dependent lysophosphatidylcholine symporter 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 59.038602 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAKGEGAESG SAAGLLPTSI LQASERPVQV KKEPKKKQQL SICNKLCYAV GGAPYQLTGC ALGFFLHIYL LDVAKVEPLP ASIILFVGR AWDAFTDPLV GFCISKSSWT RLGRLMPWII FSTPLAIIAY FLIWFVPDFP SGTESSHGFL WYLLFYCLFE T LVTCFHVP ...String:
MAKGEGAESG SAAGLLPTSI LQASERPVQV KKEPKKKQQL SICNKLCYAV GGAPYQLTGC ALGFFLHIYL LDVAKVEPLP ASIILFVGR AWDAFTDPLV GFCISKSSWT RLGRLMPWII FSTPLAIIAY FLIWFVPDFP SGTESSHGFL WYLLFYCLFE T LVTCFHVP YSALTMFIST EQSERDSATA YRMTVEVLGT VIGTAIQGQI VGQAKAPCLQ DQNGSVVVSE VANRTQSTAS LK DTQNAYL LAAGIIASIY VLCAFILILG VREQRELYES QQAESMPFFQ GLRLVMGHGP YVKLIAGFLF TSLAFMLVEG NFA LFCTYT LDFRNEFQNL LLAIMLSATF TIPIWQWFLT RFGKKTAVYI GISSAVPFLI LVALMERNLI VTYVVAVAAG VSVA AAFLL PWSMLPDVID DFHLKHPHSP GTEPIFFSFY VFFTKFASGV SLGVSTLSLD FANYQRQGCS QPEQVKFTLK MLVTM APII LILLGLLLFK LYPIDEEKRR QNKKALQALR EEASSSGCSD TDSTELASIL

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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

Concentration5 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R2/1 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 96 % / Chamber temperature: 293 K / Instrument: LEICA EM GP

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 90577
FSC plot (resolution estimation)

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