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- PDB-7n98: Cryo-EM structure of MFSD2A -

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Basic information

Entry
Database: PDB / ID: 7n98
TitleCryo-EM structure of MFSD2A
ComponentsSodium-dependent lysophosphatidylcholine symporter 1
KeywordsTRANSPORT PROTEIN / membrane protein
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsZhang, J. / Feng, L.
Funding support United States, 1items
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, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 4, 2021Provider: repository / Type: Initial release
Revision 1.1Aug 25, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Sep 1, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

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Assembly

Deposited unit
A: Sodium-dependent lysophosphatidylcholine symporter 1


Theoretical massNumber of molelcules
Total (without water)59,0391
Polymers59,0391
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area0 Å2
ΔGint0 kcal/mol
Surface area24560 Å2

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Components

#1: Protein Sodium-dependent lysophosphatidylcholine symporter 1 / NLS1 / Sodium-dependent LPC symporter 1 / Major facilitator superfamily domain-containing protein 2A


Mass: 59038.602 Da / Num. of mol.: 1 / Mutation: Q67H
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Mfsd2a, Mfsd2, Nls1 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q9DA75

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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: membrane protein complexBiological membrane / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightUnits: KILODALTONS/NANOMETER / Experimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293
Buffer solutionpH: 7.5
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/1
VitrificationInstrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 96 % / Chamber temperature: 293 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
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 90577 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0043725
ELECTRON MICROSCOPYf_angle_d0.685084
ELECTRON MICROSCOPYf_dihedral_angle_d21.9502
ELECTRON MICROSCOPYf_chiral_restr0.046598
ELECTRON MICROSCOPYf_plane_restr0.006628

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