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TGM6-D3 bound to mouse TBRII
Structural highlights
Publication Abstract from PubMedHeligmosomoides polygyrus, a mouse parasite, modulates host immunity by secreting modular transforming growth factor-beta (TGFbeta) mimics (TGMs). The agonist TGM1 interacts with TGFBR1, TGFBR2, and the co-receptor CD44 through domains D1/2, D3, and D4/5, respectively. In contrast, the antagonist TGM6, which lacks D1/2, but retains TGFBR2 binding through D3, targets different cells compared to TGM1. The TGM6 co-receptor is unknown. Using X-ray crystallography and binding studies, we show that TGM6 preferentially binds mouse TGFBR2 over human TGFBR2, and that this is essential for its antagonistic function. We identified low-density lipoprotein receptor-related protein 1 (LRP1) and betaglycan (TGFBR3) as co-receptors for TGM6. LRP1 enhances TGM6 efficacy and is required for its antagonistic effect by promoting TGFBR2 lysosomal degradation, whereas betaglycan counteracts TGM6 in a TGFBR2-dependent manner. The modular organization of TGMs enabled us to design TGM1/6 chimeras or TGM-D3 fusion with an affibody that recognizes a specific cell-surface receptor, thereby altering cell-type specificity and functionality. Furthermore, we developed a TGFBR2 nanobody that, on its own, has no inhibitory effect but, when fused to a receptor antibody, antagonizes TGFbeta by blocking TGFbeta receptor interaction in a cell-selective manner. Thus, we designed programmable agents that modulate TGFbeta signaling only in co-receptor-expressing cells. Decoding the Mechanism of Action of a Parasite TGFbeta Antagonist Inspires the Creation of Cell-Type-Specific TGFbeta Modulators.,van Dinther M, Schwartze T, Zhang J, Fan K, van der Zon G, Power L, Hinck CS, Ciancia C, Mukundan A, Gonzalez-Prieto R, van Veelen P, Maizels RM, Hinck AP, Ten Dijke P Adv Sci (Weinh). 2026 Apr 20:e75322. doi: 10.1002/advs.75322. PMID:42003773[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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