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- EMDB-7441: CryoEM structure of human SLC4A4 sodium-coupled acid-base transpo... -

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Basic information

Entry
Database: EMDB / ID: EMD-7441
TitleCryoEM structure of human SLC4A4 sodium-coupled acid-base transporter NBCe1
Map dataElectrogenic Sodium Bicarbonate Cotransporter, SLC4A4, NBCe1
Sample
  • Complex: NBCe1 Dimer
    • Protein or peptide: Electrogenic sodium bicarbonate cotransporter 1
KeywordsSLC4A4 / Electrogenic Sodium-Coupled Bicarbonate Cotransporters / TRANSPORT PROTEIN / NBCe1
Function / homology
Function and homology information


Defective SLC4A4 causes renal tubular acidosis, proximal, with ocular abnormalities and mental retardation (pRTA-OA) / sodium:bicarbonate symporter activity / monoatomic ion homeostasis / Bicarbonate transporters / sodium ion export across plasma membrane / solute:inorganic anion antiporter activity / symporter activity / bicarbonate transport / sodium ion transport / plasma membrane => GO:0005886 ...Defective SLC4A4 causes renal tubular acidosis, proximal, with ocular abnormalities and mental retardation (pRTA-OA) / sodium:bicarbonate symporter activity / monoatomic ion homeostasis / Bicarbonate transporters / sodium ion export across plasma membrane / solute:inorganic anion antiporter activity / symporter activity / bicarbonate transport / sodium ion transport / plasma membrane => GO:0005886 / transport across blood-brain barrier / transmembrane transporter activity / sodium ion transmembrane transport / positive regulation of glycolytic process / regulation of membrane potential / regulation of intracellular pH / transmembrane transport / basolateral plasma membrane / cell surface / extracellular exosome / membrane / identical protein binding / plasma membrane
Similarity search - Function
Sodium bicarbonate cotransporter / Band 3 cytoplasmic domain / Band 3 cytoplasmic domain / Bicarbonate transporter, eukaryotic / Bicarbonate transporter-like, transmembrane domain / HCO3- transporter integral membrane domain / Phosphotransferase/anion transporter
Similarity search - Domain/homology
Electrogenic sodium bicarbonate cotransporter 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsHuynh KW / Jiang J
Funding support United States, 11 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK077162 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK007789 United States
Allan Smidt Charitable Fund United States
Factor Family Foundation United States
Ralph Block Family Foundation United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM071940 United States
National Institutes of Health/National Institute of Dental and Craniofacial Research (NIH/NIDCR)DE025567 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI094386 United States
National Institutes of Health/National Center for Research Resources (NIH/NCRR)1S10RR23057 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1U24GM116792 United States
National Science Foundation (NSF, United States)DBI-1338135 United States
CitationJournal: Nat Commun / Year: 2018
Title: CryoEM structure of the human SLC4A4 sodium-coupled acid-base transporter NBCe1.
Authors: Kevin W Huynh / Jiansen Jiang / Natalia Abuladze / Kirill Tsirulnikov / Liyo Kao / Xuesi Shao / Debra Newman / Rustam Azimov / Alexander Pushkin / Z Hong Zhou / Ira Kurtz /
Abstract: Na-coupled acid-base transporters play essential roles in human biology. Their dysfunction has been linked to cancer, heart, and brain disease. High-resolution structures of mammalian Na-coupled acid- ...Na-coupled acid-base transporters play essential roles in human biology. Their dysfunction has been linked to cancer, heart, and brain disease. High-resolution structures of mammalian Na-coupled acid-base transporters are not available. The sodium-bicarbonate cotransporter NBCe1 functions in multiple organs and its mutations cause blindness, abnormal growth and blood chemistry, migraines, and impaired cognitive function. Here, we have determined the structure of the membrane domain dimer of human NBCe1 at 3.9 Å resolution by cryo electron microscopy. Our atomic model and functional mutagenesis revealed the ion accessibility pathway and the ion coordination site, the latter containing residues involved in human disease-causing mutations. We identified a small number of residues within the ion coordination site whose modification transformed NBCe1 into an anion exchanger. Our data suggest that symporters and exchangers utilize comparable transport machinery and that subtle differences in their substrate-binding regions have very significant effects on their transport mode.
History
DepositionJan 29, 2018-
Header (metadata) releaseMar 7, 2018-
Map releaseMar 7, 2018-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.075
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.075
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6caa
  • Surface level: 0.075
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_7441.png

Downloads & links

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Map

FileDownload / File: emd_7441.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationElectrogenic Sodium Bicarbonate Cotransporter, SLC4A4, NBCe1
Voxel sizeX=Y=Z: 1.36 Å
Density
Contour LevelBy AUTHOR: 0.075 / Movie #1: 0.075
Minimum - Maximum-0.21364401 - 0.41390547
Average (Standard dev.)0.00007420711 (±0.010444199)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions192192192
Spacing192192192
CellA=B=C: 261.12 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.361.361.36
M x/y/z192192192
origin x/y/z0.0000.0000.000
length x/y/z261.120261.120261.120
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS192192192
D min/max/mean-0.2140.4140.000

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Supplemental data

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Sample components

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Entire : NBCe1 Dimer

EntireName: NBCe1 Dimer
Components
  • Complex: NBCe1 Dimer
    • Protein or peptide: Electrogenic sodium bicarbonate cotransporter 1

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Supramolecule #1: NBCe1 Dimer

SupramoleculeName: NBCe1 Dimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human) / Organ: Kidney
Molecular weightTheoretical: 260 KDa

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Macromolecule #1: Electrogenic sodium bicarbonate cotransporter 1

MacromoleculeName: Electrogenic sodium bicarbonate cotransporter 1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Organ: Kidney
Molecular weightTheoretical: 116.172312 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSTENVEGKP SNLGERGRAR SSTFLRVVQP MFNHSIFTSA VSPAAERIRF ILGEEDDSPA PPQLFTELDE LLAVDGQEME WKETARWIK FEEKVEQGGE RWSKPHVATL SLHSLFELRT CMEKGSIMLD REASSLPQLV EMIVDHQIET GLLKPELKDK V TYTLLRKH ...String:
MSTENVEGKP SNLGERGRAR SSTFLRVVQP MFNHSIFTSA VSPAAERIRF ILGEEDDSPA PPQLFTELDE LLAVDGQEME WKETARWIK FEEKVEQGGE RWSKPHVATL SLHSLFELRT CMEKGSIMLD REASSLPQLV EMIVDHQIET GLLKPELKDK V TYTLLRKH RHQTKKSNLR SLADIGKTVS SASRMFTNPD NGSPAMTHRN LTSSSLNDIS DKPEKDQLKN KFMKKLPRDA EA SNVLVGE VDFLDTPFIA FVRLQQAVML GALTEVPVPT RFLFILLGPK GKAKSYHEIG RAIATLMSDE VFHDIAYKAK DRH DLIAGI DEFLDEVIVL PPGEWDPAIR IEPPKSLPSS DKRKNMYSGG ENVQMNGDTP HDGGHGGGGH GDCEELQRTG RFCG GLIKD IKRKAPFFAS DFYDALNIQA LSAILFIYLA TVTNAITFGG LLGDATDNMQ GVLESFLGTA VSGAIFCLFA GQPLT ILSS TGPVLVFERL LFNFSKDNNF DYLEFRLWIG LWSAFLCLIL VATDASFLVQ YFTRFTEEGF SSLISFIFIY DAFKKM IKL ADYYPINSNF KVGYNTLFSC TCVPPDPANI SISNDTTLAP EYLPTMSSTD MYHNTTFDWA FLSKKECSKY GGNLVGN NC NFVPDITLMS FILFLGTYTS SMALKKFKTS PYFPTTARKL ISDFAIILSI LIFCVIDALV GVDTPKLIVP SEFKPTSP N RGWFVPPFGE NPWWVCLAAA IPALLVTILI FMDQQITAVI VNRKEHKLKK GAGYHLDLFW VAILMVICSL MALPWYVAA TVISIAHIDS LKMETETSAP GEQPKFLGVR EQRVTGTLVF ILTGLSVFMA PILKFIPMPV LYGVFLYMGV ASLNGVQFMD RLKLLLMPL KHQPDFIYLR HVPLRRVHLF TFLQVLCLAL LWILKSTVAA IIFPVMILAL VAVRKGMDYL FSQHDLSFLD D VIPEKDKK KKEDEKKKKK KKGSLDSDND DSDCPYSEKV PSIKIPMDIM EQQPFLSDSK PSDRERSPTF LERHTSC

UniProtKB: Electrogenic sodium bicarbonate cotransporter 1

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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

Concentration0.40 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
20.0 mMC4H12ClNO3Tris-HClTris
150.0 mMNaClSodium chloridesodium chloride
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV
DetailsSample was purified in DDM and exchanged into Amphipols (PMAL-C8)

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsCalibrated magnification: 36764 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm
Specialist opticsEnergy filter - Name: GIF Quantum LS / Energy filter - Lower energy threshold: 0 eV / Energy filter - Upper energy threshold: 20 eV
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Frames/image: 2-36 / Number grids imaged: 2 / Number real images: 3378 / Average electron dose: 24.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1729419
Startup modelType of model: OTHER / Details: Used a oval-shaped disk low-passed filtered to 60A
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 2.0)
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION (ver. 2.0)
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 2.0) / Number images used: 184561
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL
Output model

PDB-6caa:
CryoEM structure of human SLC4A4 sodium-coupled acid-base transporter NBCe1

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