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- PDB-9irc: CyroEM structure of hSLC15A4+TASL+Fab235 -

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Basic information

Entry
Database: PDB / ID: 9irc
TitleCyroEM structure of hSLC15A4+TASL+Fab235
Components
  • Fab235 heavy chain
  • Fab235 light chain
  • Solute carrier family 15 member 4
  • TLR adapter interacting with SLC15A4 on the lysosome
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / hSLC15A4+TASL+Fab235 complex / membrane protein / antibody / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.82 Å
AuthorsZhu, Y.L. / Zhang, Q.X. / Gao, P.
Funding support China, 1items
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, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 20, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Solute carrier family 15 member 4
B: TLR adapter interacting with SLC15A4 on the lysosome
H: Fab235 heavy chain
L: Fab235 light chain


Theoretical massNumber of molelcules
Total (without water)109,1914
Polymers109,1914
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Solute carrier family 15 member 4 / Peptide transporter 4 / Peptide/histidine transporter 1 / hPHT1


Mass: 64834.129 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC15A4, PHT1, PTR4, FP12591 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8N697
#2: Protein TLR adapter interacting with SLC15A4 on the lysosome


Mass: 19437.514 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Tasl / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9D3J9
#3: Antibody Fab235 heavy chain


Mass: 13300.902 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#4: Antibody Fab235 light chain


Mass: 11618.902 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
Has protein modificationY

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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: hSLC15A4+TASL+Fab235 / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.82 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 226165 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0035731
ELECTRON MICROSCOPYf_angle_d0.5927788
ELECTRON MICROSCOPYf_dihedral_angle_d4.338778
ELECTRON MICROSCOPYf_chiral_restr0.042884
ELECTRON MICROSCOPYf_plane_restr0.004963

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