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TitleMapping the extracellular molecular architecture of the pAg-signaling complex with α-Butyrophilin antibodies.
Journal, issue, pagesSci Rep, Vol. 15, Issue 1, Page 12162, Year 2025
Publish dateApr 9, 2025
AuthorsAmrita Ramesh / Sobhan Roy / Tomasz Slezak / James Fuller / Hortencia Graves / Murad R Mamedov / Alexander Marson / Anthony A Kossiakoff / Erin J Adams /
PubMed AbstractTarget cells trigger Vγ9Vδ2 T cell activation by signaling the intracellular accumulation of phospho-antigen metabolites (pAgs) through Butyrophilin (BTN)-3A1 and BTN2A1 to the Vγ9Vδ2 T cell ...Target cells trigger Vγ9Vδ2 T cell activation by signaling the intracellular accumulation of phospho-antigen metabolites (pAgs) through Butyrophilin (BTN)-3A1 and BTN2A1 to the Vγ9Vδ2 T cell receptor (TCR). An incomplete understanding of the molecular dynamics in this signaling complex hampers Vγ9Vδ2 T cell immunotherapeutic efficacy. A panel of engineered α-BTN3A1 and α-BTN2A1 antibody (mAb) reagents was used to probe the roles of BTN3A1 and BTN2A1 in pAg signaling. Modified α-BTN3A1 mAbs with increased inter-Fab distances establish that tight clustering of BTN3A1 is not necessary to stimulate Vγ9Vδ2 T cell activation, and that antagonism may occur through occlusion of a critical binding interaction between BTN3A1 and a yet unknown co-receptor. Finally, a panel of additional α-BTN2A1 antagonists utilize different biophysical mechanisms to compete with Vγ9Vδ2 TCRs for BTN2A1 binding. The complex structures of BTN2A1 ectodomain and Fabs from three antagonist mAbs provide molecular insights into BTN2A1 epitopes critical for pAg-signaling.
External linksSci Rep / PubMed:40204806 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.76 - 3.86 Å
Structure data

47104

9dpe

EMDB-47104, PDB-9dpe:
CryoEM Structure of Human BTN2A1 ectodomain in complex with TCR-blocking 2A1.12 Fab
Method: EM (single particle) / Resolution: 3.86 Å

PDB-8vc7:
Crystal Structure of Human BTN2A1 ectodomain in complex with Antagonist 2A1.9 Fab
Method: X-RAY DIFFRACTION / Resolution: 2.76 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / Inhibitor / Complex / Antibody / Immune Recognition / IMMUNE SYSTEM

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