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TitleDevelopment of conformation-selective antibodies targeting human SLC15A4.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 7324, Year 2025
Publish dateAug 8, 2025
AuthorsYalan 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 /
PubMed AbstractSLC15A4, 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.
External linksNat Commun / PubMed:40781080 / PubMed Central
MethodsEM (single particle)
Resolution2.82 - 3.15 Å
Structure data

EMDB-60808, PDB-9irb:
CryoEM structure of hSLC15A4+Fab107
Method: EM (single particle) / Resolution: 3.15 Å

EMDB-60809, PDB-9irc:
CyroEM structure of hSLC15A4+TASL+Fab235
Method: EM (single particle) / Resolution: 2.82 Å

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / hSLC15A4+Fab107 complex / membrane protein / antibody / MEMBRANE PROTEIN-IMMUNE SYSTEM complex / hSLC15A4+TASL+Fab235 complex

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