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- PDB-7mjs: Single-Particle Cryo-EM Structure of Major Facilitator Superfamil... -

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Basic information

Entry
Database: PDB / ID: 7mjs
TitleSingle-Particle Cryo-EM Structure of Major Facilitator Superfamily Domain containing 2A in complex with LPC-18:3
Components
  • 2AG3 Fab heavy chain
  • 2AG3 Fab light chain
  • Major Facilitator Superfamily Domain containing 2A
KeywordsLIPID TRANSPORT/IMMUNE SYSTEM / MFS transporters / lysolipids / blood-brain barrier / omega-3 fatty acids / LIPID TRANSPORT-IMMUNE SYSTEM complex
Function / homology
Function and homology information


Synthesis of PC / 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 ...Synthesis of PC / 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 / photoreceptor cell outer segment organization / lipid transport across blood-brain barrier / 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 / establishment of blood-brain barrier / transcytosis / motor behavior / maintenance of blood-brain barrier / plasma membrane => GO:0005886 / regulation of multicellular organism growth / carbohydrate transport / energy homeostasis / cellular response to starvation / hippocampus development / cognition / positive regulation of cell growth
Similarity search - Function
Lactose permease-like / MFS transporter superfamily
Similarity search - Domain/homology
Chem-ZGS / Uncharacterized protein
Similarity search - Component
Biological speciesSynthetic construct (others)
Gallus gallus (chicken)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.03 Å
AuthorsCater, R.J. / Chua, G.L. / Erramilli, S.K. / Keener, J.E. / Choy, B.C. / Tokarz, P. / Chin, C.F. / Quek, D.Q.Y. / Kloss, B. / Pepe, J.G. ...Cater, R.J. / Chua, G.L. / Erramilli, S.K. / Keener, J.E. / Choy, B.C. / Tokarz, P. / Chin, C.F. / Quek, D.Q.Y. / Kloss, B. / Pepe, J.G. / Parisi, G. / Wong, B.H. / Clarke, O.B. / Marty, M.T. / Kossiakoff, A.A. / Khelashvili, G. / Silver, D.L. / Mancia, F.
Funding support United States, Singapore, 7items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM132120 United States
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)MH12564 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM128624 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM117372 United States
National Research Foundation (NRF, Singapore)NRF-NRFI2017-05 Singapore
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM116799 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM103310 United States
CitationJournal: Nature / Year: 2021
Title: Structural basis of omega-3 fatty acid transport across the blood-brain barrier.
Authors: Rosemary J Cater / Geok Lin Chua / Satchal K Erramilli / James E Keener / Brendon C Choy / Piotr Tokarz / Cheen Fei Chin / Debra Q Y Quek / Brian Kloss / Joseph G Pepe / Giacomo Parisi / ...Authors: Rosemary J Cater / Geok Lin Chua / Satchal K Erramilli / James E Keener / Brendon C Choy / Piotr Tokarz / Cheen Fei Chin / Debra Q Y Quek / Brian Kloss / Joseph G Pepe / Giacomo Parisi / Bernice H Wong / Oliver B Clarke / Michael T Marty / Anthony A Kossiakoff / George Khelashvili / David L Silver / Filippo Mancia /
Abstract: Docosahexaenoic acid is an omega-3 fatty acid that is essential for neurological development and function, and it is supplied to the brain and eyes predominantly from dietary sources. This nutrient ...Docosahexaenoic acid is an omega-3 fatty acid that is essential for neurological development and function, and it is supplied to the brain and eyes predominantly from dietary sources. This nutrient is transported across the blood-brain and blood-retina barriers in the form of lysophosphatidylcholine by major facilitator superfamily domain containing 2A (MFSD2A) in a Na-dependent manner. Here we present the structure of MFSD2A determined using single-particle cryo-electron microscopy, which reveals twelve transmembrane helices that are separated into two pseudosymmetric domains. The transporter is in an inward-facing conformation and features a large amphipathic cavity that contains the Na-binding site and a bound lysolipid substrate, which we confirmed using native mass spectrometry. Together with our functional analyses and molecular dynamics simulations, this structure reveals details of how MFSD2A interacts with substrates and how Na-dependent conformational changes allow for the release of these substrates into the membrane through a lateral gate. Our work provides insights into the molecular mechanism by which this atypical major facility superfamily transporter mediates the uptake of lysolipids into the brain, and has the potential to aid in the delivery of neurotherapeutic agents.
History
DepositionApr 20, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 16, 2021Provider: repository / Type: Initial release
Revision 1.1Jul 14, 2021Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Jul 28, 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
H: 2AG3 Fab heavy chain
L: 2AG3 Fab light chain
X: Major Facilitator Superfamily Domain containing 2A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)111,0526
Polymers110,0913
Non-polymers9613
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: Cryo-EM and native mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area4420 Å2
ΔGint-23 kcal/mol
Surface area29820 Å2

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Components

#1: Antibody 2AG3 Fab heavy chain


Mass: 25646.537 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Synthetic construct (others) / Production host: Escherichia coli (E. coli)
#2: Antibody 2AG3 Fab light chain


Mass: 23655.182 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Synthetic construct (others) / Production host: Escherichia coli (E. coli)
#3: Protein Major Facilitator Superfamily Domain containing 2A


Mass: 60789.168 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Gallus gallus (chicken) / Gene: MFSD2A / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: F1NCD6
#4: Chemical ChemComp-ZGS / [(2~{R})-2-oxidanyl-3-[oxidanyl-[2-(trimethyl-$l^{4}-azanyl)ethoxy]phosphoryl]oxy-propyl] (9~{Z},12~{Z},15~{Z})-octadeca-9,12,15-trienoate / LysoPC(18:3(9Z,12Z,15Z))


Mass: 518.644 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C26H49NO7P / Feature type: SUBJECT OF INVESTIGATION
#5: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
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: Single-Particle Cryo-EM Structure of Major Facilitator Superfamily Domain containing 2A (MFSD2A) Gallus gallus in complex with LPC-18:3
Type: COMPLEX / Entity ID: #1-#3 / Source: MULTIPLE SOURCES
Molecular weightUnits: MEGADALTONS / Experimental value: NO
Source (natural)Organism: Gallus gallus (chicken)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm) / Strain: SF9
Buffer solutionpH: 7
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: FEI TITAN
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingAverage exposure time: 3 sec. / Electron dose: 58 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
Image scansSampling size: 5 µm / Width: 5760 / Height: 4092

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Processing

CTF correctionDetails: Patch CTF / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 175738 / Symmetry type: POINT

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