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- EMDB-54661: Cryo-EM structure of Rat NHE6 in nanodisc -

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Entry
Database: EMDB / ID: EMD-54661
TitleCryo-EM structure of Rat NHE6 in nanodisc
Map data
Sample
  • Complex: Dimeric Rat NHE6 in nanodisc
    • Protein or peptide: Sodium/hydrogen exchanger 6
KeywordsNa+/H+ exchanger / Nhe6 / TRANSPORT PROTEIN
Biological speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.25 Å
AuthorsYeo H / Jung S / Reichenbach T / Kokane S / Gulati A / Drew D
Funding supportEuropean Union, Sweden, 2 items
OrganizationGrant numberCountry
European Research Council (ERC)European Union
Knut and Alice Wallenberg Foundation Sweden
CitationJournal: Nat Commun / Year: 2026
Title: Structure of NHE6 and its lipid-mediated interactions regulating endosomal pH.
Authors: Sukkyeong Jung / Hyunku Yeo / Hang Li / Surabhi Kokane / Tom Reichenbach / Ashutosh Gulati / Giuseppe Albano / Carla Kirschbaum / Tin Manh Ho / Michael Landreh / Mia Abramsson / Carol V ...Authors: Sukkyeong Jung / Hyunku Yeo / Hang Li / Surabhi Kokane / Tom Reichenbach / Ashutosh Gulati / Giuseppe Albano / Carla Kirschbaum / Tin Manh Ho / Michael Landreh / Mia Abramsson / Carol V Robinson / Daniel G Fuster / David Drew /
Abstract: Sodium-proton exchangers (NHEs) are found in all cells to regulate intracellular pH, sodium levels and cell volume. In humans, there are nine different NHE transporters (SLC9A1-9), which vary in ...Sodium-proton exchangers (NHEs) are found in all cells to regulate intracellular pH, sodium levels and cell volume. In humans, there are nine different NHE transporters (SLC9A1-9), which vary in tissue distribution, kinetics and regulation. NHE6 localizes to endosomal membranes and mutations in the protein are known to cause the X-linked neurological disorder Christianson syndrome. Despite its importance, the structural basis of NHE6 function and regulation is unclear. Here we report four cryo-electron microscopy structures of rat NHE6 between 2.2 and 3.3 Å resolution, revealing its homodimeric structure, ion binding and remodelling by lipids. We characterize a lipid-binding site between the protomers that accommodates the endosomal-specific phosphatidylinositol 3-phosphate (PI3P) lipid. Using solid-supported membrane (SSM)-based electrophysiology we demonstrate that NHE6 transports both Na and K ions and that PI3P enhances NHE6 stability and activity. Furthermore, we identify a phosphatidylinositol 4,5-bisphosphate (PI(4,5)P) lipid, which interacts with the C-terminal domain of NHE6 to stabilize an auto-inhibited state. We further demonstrate that NHE6 is non-functional when mislocalized to the plasma membrane where PI(4,5)P is primarily located. We propose the lipid-dependent regulation has evolved to shut-down NHE6 activity during recycling of endosomes at the plasma membrane.
History
DepositionAug 5, 2025-
Header (metadata) releaseJul 29, 2026-
Map releaseJul 29, 2026-
UpdateAug 26, 2026-
Current statusAug 26, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_54661.png

Downloads & links

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Map

FileDownload / File: emd_54661.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.66 Å/pix.
x 384 pix.
= 255.168 Å		0.66 Å/pix.
x 384 pix.
= 255.168 Å		0.66 Å/pix.
x 384 pix.
= 255.168 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.6645 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.034
Minimum - Maximum-0.06308703 - 0.14244011
Average (Standard dev.)-0.00003962612 (±0.0036938689)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 255.168 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_54661_msk_1.map
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Half map: #1

Fileemd_54661_half_map_1.map
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Half map: #2

Fileemd_54661_half_map_2.map
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Sample components

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Entire : Dimeric Rat NHE6 in nanodisc

EntireName: Dimeric Rat NHE6 in nanodisc
Components
  • Complex: Dimeric Rat NHE6 in nanodisc
    • Protein or peptide: Sodium/hydrogen exchanger 6

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Supramolecule #1: Dimeric Rat NHE6 in nanodisc

SupramoleculeName: Dimeric Rat NHE6 in nanodisc / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Rattus norvegicus (Norway rat)

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Macromolecule #1: Sodium/hydrogen exchanger 6

MacromoleculeName: Sodium/hydrogen exchanger 6 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 78.876438 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAVARRGWRL APVRRGVCGP RARLLMRPLW LLFAVSFFGW AGALDSSGGT TRAMDEEIVS EKQAEESHRQ DSANLLIFIL LLTLTILTI WLFKHRRARF LHETGLAMIY GLLVGLVLRY GIHVPSDVNN VTLSCEVQSS PTTLLVNVSG KFYEYTLKGE I SSHELNNV ...String:
MAVARRGWRL APVRRGVCGP RARLLMRPLW LLFAVSFFGW AGALDSSGGT TRAMDEEIVS EKQAEESHRQ DSANLLIFIL LLTLTILTI WLFKHRRARF LHETGLAMIY GLLVGLVLRY GIHVPSDVNN VTLSCEVQSS PTTLLVNVSG KFYEYTLKGE I SSHELNNV QDNEMLRKVT FDPEVFFNIL LPPIIFYAGY SLKRRHFFRN LGSILAYAFL GTAISCFVIG SIMYGCVTLM KV TGQLAGD FYFTDCLLFG AIVSATDPVT VLAIFHELQV DVELYALLFG ESVLNDAVAI VLSSSIVAYQ PAGDNSHTFD VTA MFKSIG IFLGIFSGSF AMGAATGVVT ALVTKFTKLR EFQLLETGLF FLMSWSTFLL AEAWGFTGVV AVLFCGITQA HYTY NNLST ESQHRTKQLF ELLNFLAENF IFSYMGLTLF TFQNHVFNPT FVVGAFIAIF LGRAANIYPL SLLLNLGRRS KIGSN FQHM MMFAGLRGAM AFALAIRDTA TYARQMMFST TLLIVFFTVW VFGGGTTAML SCLHIRVGVD SDQEHLGVPD NERRTT KAE SAWLFRMWYN FDHNYLKPLL THSGPPLTTT LPACCGPIAR CLTSPQAYEN QEQLKDDDSD LILNDGDISL TYGDSTV NT ESATASAPRR FMGTSTEDAL DRELTFGDHE LVIRGTRLVL PMDDSEPALN SLDDTRHSPA ENLYFQ

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 63.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 0.4 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.25 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 127174
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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