Structural and evolutionary insights into DAF-12 interactions with transcriptional coactivators in parasitic nematodes
Abstract
Parasitic nematodes infect billions of humans and livestock worldwide, causing major health and economic burdens, while the spread of anthelmintic resistance threatens current control strategies. A critical step in parasite infection is the resumption of development of infective third-stage larvae (iL3) upon host entry, a process controlled by the nuclear receptor DAF-12. Activation of DAF-12 by dafachronic acids promotes developmental progression and reproductive maturation, making this receptor an attractive therapeutic target. However, the molecular mechanisms governing DAF-12 activation, particularly transcriptional coactivator recruitment, remain poorly understood. Here, we combined biophysical, cellular, structural, and bioinformatic approaches to investigate coactivator recognition by DAF-12 from the parasitic nematodes Brugia malayi and Haemonchus contortus. Crystal structures of ligand-bound DAF-12 ligand-binding domains in complex with coactivator-derived peptides reveal conserved features of ligand-dependent coactivator recruitment shared with mammalian nuclear receptors. In addition, we uncover previously unrecognized interaction features, including motif-specific contacts that extend beyond the canonical LXXLL binding mode of coactivators and distinct patterns of DAF-12 conservation across nematode clades. Structure-guided analyses redefine the interaction motif of the only described parasite-specific coactivator DIP-1 and suggest novel candidate motifs for DAF-12-interacting proteins. Together, these findings establish the structural basis of coactivator binding to nematode DAF-12 and provide mechanistic insight into the transcriptional regulation underlying parasite development. These results expand current understanding of nuclear receptor signaling in parasitic nematodes and provide a framework for the future design of strategies aimed at disrupting DAF-12 activation as a potential antiparasitic approach.
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BibTeX
@article{mallet2026structural,
title = {{Structural and evolutionary insights into DAF-12 interactions with transcriptional coactivators in parasitic nematodes}},
author = {Manon Mallet and Yéléna Martin and João E Carvalho and Eva Guchen and Remy Betous and Cherine Bechara and Anne Lespine and Michael Schubert and William Bourguet and Albane Le Maire},
journal = {PLoS Pathogens},
year = {2026},
month = jul,
doi = {10.1371/journal.ppat.1014073},
url = {https://hal.science/hal-05701198v2},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Structural and evolutionary insights into DAF-12 interactions with transcriptional coactivators in parasitic nematodes
AU - Manon Mallet
AU - Yéléna Martin
AU - João E Carvalho
AU - Eva Guchen
AU - Remy Betous
AU - Cherine Bechara
AU - Anne Lespine
AU - Michael Schubert
AU - William Bourguet
AU - Albane Le Maire
PY - 2026
DA - 2026/07/20
JO - PLoS Pathogens
DO - 10.1371/journal.ppat.1014073
UR - https://hal.science/hal-05701198v2
AB - Parasitic nematodes infect billions of humans and livestock worldwide, causing major health and economic burdens, while the spread of anthelmintic resistance threatens current control strategies. A critical step in parasite infection is the resumption of development of infective third-stage larvae (iL3) upon host entry, a process controlled by the nuclear receptor DAF-12. Activation of DAF-12 by dafachronic acids promotes developmental progression and reproductive maturation, making this receptor an attractive therapeutic target. However, the molecular mechanisms governing DAF-12 activation, particularly transcriptional coactivator recruitment, remain poorly understood. Here, we combined biophysical, cellular, structural, and bioinformatic approaches to investigate coactivator recognition by DAF-12 from the parasitic nematodes Brugia malayi and Haemonchus contortus. Crystal structures of ligand-bound DAF-12 ligand-binding domains in complex with coactivator-derived peptides reveal conserved features of ligand-dependent coactivator recruitment shared with mammalian nuclear receptors. In addition, we uncover previously unrecognized interaction features, including motif-specific contacts that extend beyond the canonical LXXLL binding mode of coactivators and distinct patterns of DAF-12 conservation across nematode clades. Structure-guided analyses redefine the interaction motif of the only described parasite-specific coactivator DIP-1 and suggest novel candidate motifs for DAF-12-interacting proteins. Together, these findings establish the structural basis of coactivator binding to nematode DAF-12 and provide mechanistic insight into the transcriptional regulation underlying parasite development. These results expand current understanding of nuclear receptor signaling in parasitic nematodes and provide a framework for the future design of strategies aimed at disrupting DAF-12 activation as a potential antiparasitic approach.
SN - 1553-7366
SN - 1553-7374
ER -