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- EMDB-54419: Cryo-EM structure of human NHE6 in C2 symmetry -

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Basic information

Entry
Database: EMDB / ID: EMD-54419
TitleCryo-EM structure of human NHE6 in C2 symmetry
Map data
Sample
  • Complex: Homodimeric human NHE6 in C2 symmetry
    • Protein or peptide: Sodium/hydrogen exchanger 6
KeywordsNHE / C2 symmetry / homodimer / transporter / TRANSPORT PROTEIN
Function / homology
Function and homology information


Defective SLC9A6 causes X-linked, syndromic mental retardation,, Christianson type (MRXSCH) / Sodium/Proton exchangers / dendrite extension / potassium:proton antiporter activity / axon extension / sodium:proton antiporter activity / sodium ion import across plasma membrane / establishment of cell polarity / neuron projection morphogenesis / regulation of intracellular pH ...Defective SLC9A6 causes X-linked, syndromic mental retardation,, Christianson type (MRXSCH) / Sodium/Proton exchangers / dendrite extension / potassium:proton antiporter activity / axon extension / sodium:proton antiporter activity / sodium ion import across plasma membrane / establishment of cell polarity / neuron projection morphogenesis / regulation of intracellular pH / sodium ion transmembrane transport / recycling endosome / recycling endosome membrane / late endosome membrane / early endosome membrane / endosome membrane / endoplasmic reticulum membrane / identical protein binding / plasma membrane
Similarity search - Function
Sodium/hydrogen exchanger 6/7/9 / Na+/H+ exchanger / Cation/H+ exchanger, CPA1 family / Cation/H+ exchanger / Sodium/hydrogen exchanger, transmembrane
Similarity search - Domain/homology
Sodium/hydrogen exchanger 6
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsFeilen LP / Sach L / Tranchant EE / Lalic MR / Havelund JF / Brauer CM / Ginsthofer M / Ostendorf J / Ma L / Morrow EM ...Feilen LP / Sach L / Tranchant EE / Lalic MR / Havelund JF / Brauer CM / Ginsthofer M / Ostendorf J / Ma L / Morrow EM / Faergeman NJ / Pedersen SF / Kragelund BB / Autzen HE
Funding support Denmark, European Union, 5 items
OrganizationGrant numberCountry
Novo Nordisk FoundationNNF20OC0060692 Denmark
The Carlsberg FoundationCF20-0533 Denmark
Independent Research Fund Denmark - Medical Sciences1131-00023B Denmark
European Research Council (ERC)101151923European Union
Danish Council for Independent Research3103-00217B Denmark
CitationJournal: Nat Commun / Year: 2026
Title: Integrative structural analysis of human endosomal NHE6 reveals a lipid-associated gate and disordered C-terminus.
Authors: Lukas P Feilen / Lara K Sach / Emil E Tranchant / Milena R Lalic / Jesper F Havelund / Céline M Jeria Cerda / Marie Ginsthofer / Jan Ostendorf / Li Ma / Eric M Morrow / Nils J Færgeman / ...Authors: Lukas P Feilen / Lara K Sach / Emil E Tranchant / Milena R Lalic / Jesper F Havelund / Céline M Jeria Cerda / Marie Ginsthofer / Jan Ostendorf / Li Ma / Eric M Morrow / Nils J Færgeman / Stine F Pedersen / Birthe B Kragelund / Henriette E Autzen /
Abstract: Human NHE6 (HsNHE6) is an endosomal Na⁺/H⁺ exchanger essential for maintaining luminal pH and endo-lysosomal trafficking in neurons. HsNHE6 mutations are implicated in devastating neurological ...Human NHE6 (HsNHE6) is an endosomal Na⁺/H⁺ exchanger essential for maintaining luminal pH and endo-lysosomal trafficking in neurons. HsNHE6 mutations are implicated in devastating neurological syndromes, but mechanistically the transporter remains poorly understood. Here, we present the single-particle cryo-electron microscopy (cryo-EM) structure of HsNHE6 at 3.4 Å, captured in an inward-facing conformation. The structure reveals a homodimeric architecture with 13 transmembrane helices per protomer, with the conserved ion-binding site located at the interface of the core and dimerization domains. Functional assays demonstrate that HsNHE6 reconstituted in liposomes exchanges Na⁺, K⁺, Li⁺, and Rb for H, with kinetic analysis revealing a preference for K⁺. A structured C-terminal helix interacts with the transmembrane core, jointly forming a hydrophobic cavity containing two non-protein cryo-EM densities consistent with bound lipids that may modulate cation access to the ion-binding site. The remaining distal C-terminus of HsNHE6 is intrinsically disordered, as revealed by NMR and small-angle X-ray scattering, and extends up to 170 Å into the cytosol. Our integrative structural model of full-length HsNHE6 provides a framework for understanding HsNHE6-mediated ion exchange and its disruption in Christianson syndrome.
History
DepositionJul 16, 2025-
Header (metadata) releaseJul 29, 2026-
Map releaseJul 29, 2026-
UpdateSep 23, 2026-
Current statusSep 23, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_54419.png

Downloads & links

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Map

FileDownload / File: emd_54419.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 384 pix.
= 278.4 Å		0.73 Å/pix.
x 384 pix.
= 278.4 Å		0.73 Å/pix.
x 384 pix.
= 278.4 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.725 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.012
Minimum - Maximum-0.057899836 - 0.0786353
Average (Standard dev.)0.0000888102 (±0.0015347213)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 278.40002 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_54419_msk_1.map
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Additional map: #1

Fileemd_54419_additional_1.map
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Half map: #1

Fileemd_54419_half_map_1.map
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Half map: #2

Fileemd_54419_half_map_2.map
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Sample components

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Entire : Homodimeric human NHE6 in C2 symmetry

EntireName: Homodimeric human NHE6 in C2 symmetry
Components
  • Complex: Homodimeric human NHE6 in C2 symmetry
    • Protein or peptide: Sodium/hydrogen exchanger 6

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Supramolecule #1: Homodimeric human NHE6 in C2 symmetry

SupramoleculeName: Homodimeric human NHE6 in C2 symmetry / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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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: Homo sapiens (human)
Molecular weightTheoretical: 77.988508 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MARRGWRRAP LRRGVGSSPR ARRLMRPLWL LLAVGVFDWA GASDGGGGEA RAMDEEIVSE KQAEESHRQD SANLLIFILL LTLTILTIW LFKHRRARFL HETGLAMIYG LLVGLVLRYG IHVPSDVNNV TLSCEVQSSP TTLLVNVSGK FYEYMLKGEI S SHELNNVQ ...String:
MARRGWRRAP LRRGVGSSPR ARRLMRPLWL LLAVGVFDWA GASDGGGGEA RAMDEEIVSE KQAEESHRQD SANLLIFILL LTLTILTIW LFKHRRARFL HETGLAMIYG LLVGLVLRYG IHVPSDVNNV TLSCEVQSSP TTLLVNVSGK FYEYMLKGEI S SHELNNVQ DNEMLRKVTF DPEVFFNILL PPIIFYAGYS LKRRHFFRNL GSILAYAFLG TAISCFVIGS IMYGCVTLMK VT GQLAGDF YFTDCLLFGA IVSATDPVTV LAIFHELQVD VELYALLFGE SVLNDAVAIV LSSSIVAYQP AGDNSHTFDV TAM FKSIGI FLGIFSGSFA MGAATGVVTA LVTKFTKLRE FQLLETGLFF LMSWSTFLLA EAWGFTGVVA VLFCGITQAH YTYN NLSTE SQHRTKQLFE LLNFLAENFI FSYMGLTLFT FQNHVFNPTF VVGAFVAIFL GRAANIYPLS LLLNLGRRSK IGSNF QHMM MFAGLRGAMA FALAIRDTAT YARQMMFSTT LLIVFFTVWV FGGGTTAMLS CLHIRVGVDS DQEHLGVPEN ERRTTK AES AWLFRMWYNF DHNYLKPLLT HSGPPLTTTL PACCGPIARC LTSPQAYENQ EQLKDDDSDL ILNDGDISLT YGDSTVN TE PATSSAPRRF MGNSSEDALD RELAFGDHEL VIRGTRLVLP MDDSEPPLNL LDNTRHGPA

UniProtKB: Sodium/hydrogen exchanger 6

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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

Concentration2.63 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
20.0 mMHEPES2-[4-(2-Hydroxyethyl)piperazin-1-yl]ethane-1-sulfonic acid
150.0 mMNaClsodium chloride
0.034 mMGDNglyco-diosgenin
0.008 mMCHScholesteryl hemisuccinate Tris salt
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 4933 / Average electron dose: 49.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 732718
CTF correctionSoftware - Name: RELION (ver. 5.0-beta) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
In silico model: The in silico model was generated using Ab initio reconstruction in RELION 5.0-beta
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5.0-beta) / Number images used: 88691
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 5.0-beta)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 5.0-beta)
FSC plot (resolution estimation)

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