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- EMDB-60809: CyroEM structure of hSLC15A4+TASL+Fab235 -

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Basic information

Entry
Database: EMDB / ID: EMD-60809
TitleCyroEM structure of hSLC15A4+TASL+Fab235
Map data
Sample
  • Complex: hSLC15A4+TASL+Fab235
    • Protein or peptide: Solute carrier family 15 member 4
    • Protein or peptide: TLR adapter interacting with SLC15A4 on the lysosome
    • Protein or peptide: Fab235 heavy chain
    • Protein or peptide: Fab235 light chain
KeywordshSLC15A4+TASL+Fab235 complex / membrane protein / antibody / MEMBRANE PROTEIN/IMMUNE SYSTEM / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


SLC15A4:TASL-dependent IRF5 activation / histidine transport / mast cell homeostasis / L-histidine transmembrane export from vacuole / L-histidine transmembrane transporter activity / peptidoglycan transmembrane transporter activity / Proton/oligopeptide cotransporters / regulation of isotype switching to IgG isotypes / positive regulation of toll-like receptor 8 signaling pathway / peptidoglycan transport ...SLC15A4:TASL-dependent IRF5 activation / histidine transport / mast cell homeostasis / L-histidine transmembrane export from vacuole / L-histidine transmembrane transporter activity / peptidoglycan transmembrane transporter activity / Proton/oligopeptide cotransporters / regulation of isotype switching to IgG isotypes / positive regulation of toll-like receptor 8 signaling pathway / peptidoglycan transport / positive regulation of toll-like receptor 7 signaling pathway / SLC15A4:TASL-dependent IRF5 activation / positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway / dipeptide import across plasma membrane / peptide:proton symporter activity / positive regulation of toll-like receptor 9 signaling pathway / dipeptide transmembrane transporter activity / regulation of lysosomal lumen pH / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway / endolysosome membrane / positive regulation of innate immune response / regulation of toll-like receptor signaling pathway / specific granule membrane / monoatomic ion transport / protein transport / early endosome membrane / lysosomal membrane / innate immune response / Neutrophil degranulation / nucleoplasm / membrane / plasma membrane / cytosol
Similarity search - Function
TASL protein / TLR adaptor interacting with SLC15A4 on the lysosome / PTR2 family proton/oligopeptide symporters signature 2. / PTR2 family proton/oligopeptide symporter, conserved site / Proton-dependent oligopeptide transporter family / POT family / MFS transporter superfamily
Similarity search - Domain/homology
Solute carrier family 15 member 4 / TLR adapter interacting with SLC15A4 on the lysosome
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.82 Å
AuthorsZhu YL / Zhang QX / Gao P
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32200989 China
CitationJournal: Nat Commun / Year: 2025
Title: Development of conformation-selective antibodies targeting human SLC15A4.
Authors: Yalan Zhu / Xuyuan Zhang / Qixiang Zhang / Panpan Sun / Kexin Liu / Xiaohua Nie / Junxiao Ma / Liwei Zhang / Yina Gao / Yong Wang / Songqing Liu / Ang Gao / Liguo Zhang / Pu Gao /
Abstract: SLC15A4, an endolysosomal solute carrier family transporter, plays a critical role in TLR7/8/9-induced immune responses through assembling a complex with the downstream adaptor TASL in a conformation- ...SLC15A4, an endolysosomal solute carrier family transporter, plays a critical role in TLR7/8/9-induced immune responses through assembling a complex with the downstream adaptor TASL in a conformation-dependent manner. Despite its close functional association and promising therapeutic potential in infections, tumors, and autoimmune diseases, the development of conformation-specific antibodies for human SLC15A4 (hSLC15A4) remains challenging. Here, using a systematic screening and validation approach, we identify a pair of conformation-selective antibodies, clones 107 and 235, targeting the endolysosomal lumen surface of hSLC15A4 with opposite conformation-regulatory activities. Specifically, clone 107 selectively binds to hSLC15A4 in a TASL binding-incompetent luminal-open state; whereas clone 235 stabilizes hSLC15A4 in a TASL binding-competent cytoplasmic-open state. Our research identifies antibodies that recognize distinct conformations of hSLC15A4, potentially enabling modulation of the TLR7/8/9 pathway and contributing to the development of targeted therapies and research tools selectively targeting hSLC15A4.
History
DepositionJul 15, 2024-
Header (metadata) releaseAug 20, 2025-
Map releaseAug 20, 2025-
UpdateAug 20, 2025-
Current statusAug 20, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_60809.png

Downloads & links

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Map

FileDownload / File: emd_60809.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1 Å/pix.
x 320 pix.
= 320. Å		1 Å/pix.
x 320 pix.
= 320. Å		1 Å/pix.
x 320 pix.
= 320. Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.471
Minimum - Maximum-0.9476654 - 2.2278464
Average (Standard dev.)-0.00021362712 (±0.042963687)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 320.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_60809_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_60809_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : hSLC15A4+TASL+Fab235

EntireName: hSLC15A4+TASL+Fab235
Components
  • Complex: hSLC15A4+TASL+Fab235
    • Protein or peptide: Solute carrier family 15 member 4
    • Protein or peptide: TLR adapter interacting with SLC15A4 on the lysosome
    • Protein or peptide: Fab235 heavy chain
    • Protein or peptide: Fab235 light chain

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Supramolecule #1: hSLC15A4+TASL+Fab235

SupramoleculeName: hSLC15A4+TASL+Fab235 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Solute carrier family 15 member 4

MacromoleculeName: Solute carrier family 15 member 4 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 64.834129 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MEGSGGGAGE RAPLLGARRA AAAAAAAGAF AGRRAACGAV LLTELLERAA FYGITSNLVL FLNGAPFCWE GAQASEALLL FMGLTYLGS PFGGWLADAR LGRARAILLS LALYLLGMLA FPLLAAPATR AALCGSARLL NCTAPGPDAA ARCCSPATFA G LVLVGLGV ...String:
MEGSGGGAGE RAPLLGARRA AAAAAAAGAF AGRRAACGAV LLTELLERAA FYGITSNLVL FLNGAPFCWE GAQASEALLL FMGLTYLGS PFGGWLADAR LGRARAILLS LALYLLGMLA FPLLAAPATR AALCGSARLL NCTAPGPDAA ARCCSPATFA G LVLVGLGV ATVKANITPF GADQVKDRGP EATRRFFNWF YWSINLGAIL SLGGIAYIQQ NVSFVTGYAI PTVCVGLAFV VF LCGQSVF ITKPPDGSAF TDMFKILTYS CCSQKRSGER QSNGEGIGVF QQSSKQSLFD SCKMSHGGPF TEEKVEDVKA LVK IVPVFL ALIPYWTVYF QMQTTYVLQS LHLRIPEISN ITTTPHTLPA AWLTMFDAVL ILLLIPLKDK LVDPILRRHG LLPS SLKRI AVGMFFVMCS AFAAGILESK RLNLVKEKTI NQTIGNVVYH AADLSLWWQV PQYLLIGISE IFASIAGLEF AYSAA PKSM QSAIMGLFFF FSGVGSFVGS GLLALVSIKA IGWMSSHTDF GNINGCYLNY YFFLLAAIQG ATLLLFLIIS VKYDHH RDH QRSRANGVPT SRRAKLGSEN LYFQGGSGGS GHHHHHHHH

UniProtKB: Solute carrier family 15 member 4

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Macromolecule #2: TLR adapter interacting with SLC15A4 on the lysosome

MacromoleculeName: TLR adapter interacting with SLC15A4 on the lysosome / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 19.437514 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MLSEGYLSGL EYWNDIHWNC ASYNEPVAGD QGKEPISNAV LNEYLEQKVV ELYKQYIMDT VFHDSSPTQI LASEFIMTNV DQISLQVSK EKNLDTSKVK DIVISHLLQL VSSEISTPSL HISQYSNITP KLGSENLYFQ GGSGGSGHHH HHHHHWSHPQ F EKWSHPQF EK

UniProtKB: TLR adapter interacting with SLC15A4 on the lysosome

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Macromolecule #3: Fab235 heavy chain

MacromoleculeName: Fab235 heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 13.300902 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
DVQLVESGGG LVQPGGSRKL SCAASGFTFS RFGMHWVRQA PEKGLEWVAY ISSGSSNIYY ADTVKGRFTI SRDNPKNTLF LQMTSLRSE DTAMYYCARS TTIIRAFFDY WGQGTTLTVS S

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Macromolecule #4: Fab235 light chain

MacromoleculeName: Fab235 light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 11.618902 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
QIVLTQSPAI MSASLGERVT MTCTASSGVS SSYLHWYQQK PGSSPRLWIY STSNLASGVP ARFSGSGSGT SYSLTISSME AEDAATYYC HQYHRSPWAF GGGTKLEIK

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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

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.82 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 226165
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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