Structure of ergosteryl-aspartate synthase reveals how an entrapped tRNA is used like a prosthetic swinging arm in the synthesis of aminoacylated sterols
Abstract
Ergosteryl-3β-O-L-aspartate synthase (ErdS) catalyzes tRNA-dependent aspartylation of ergosterol, a lipid essential for fungal cell membrane integrity. However, the functional significance of ergosteryl-aspartate and the molecular mechanisms underlying its synthesis remain unclear. Here, we show that ErdS localization is highly dynamic and that Erg-Asp is required for proper hyphal growth, sporulation, and spore germination, and likely influences stress tolerance. The cryo-electron microscopy structure of ErdS revealed an unprecedented sterol-binding pocket. In addition, the structures in complex with a non-hydrolyzable Asp-N-tRNAAsp show a tRNA-guided intramolecular aminoacyl transfer mechanism between two functional domains of the enzyme. The CCA end of tRNAAsp undergoes a large displacement to reach the aa-tRNA transfer active site, while the tRNA elbow is clamped by a long extension an N-terminal α-helix. The present structural and mutational analyses demonstrate that domain fusion, dynamic repositioning, and tRNA-mediated substrate handover underlie the multifunctional catalytic efficiency of ErdS and participates in Erg-Asp synthesis independently from protein synthesis. These findings elucidate the regulatory mechanism of tRNA-dependent sterol modification and provide insights into fungal membrane dynamics, highlighting potential targets for antifungal therapies.
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BibTeX
@article{murayama2026structure,
title = {{Structure of ergosteryl-aspartate synthase reveals how an entrapped tRNA is used like a prosthetic swinging arm in the synthesis of aminoacylated sterols}},
author = {Hanako Murayama and Nathaniel Yakobov and Nassira Mahmoudi and Sasha Legrosdidier and Nicolas Fournier and Solène Zuttion and Kanata Matsumoto and Michihiro Nishimura and Jingwei Ji and Bruno Senger and Laurence Huck and Howard Gamper and Yoshiaki Kise and Ralph Kleiner and Mathieu Frechin and Ya-Ming Hou and Hubert Becker and Yuzuru Itoh and Frédéric Fischer and Osamu Nureki},
journal = {Nature Communications},
year = {2026},
month = may,
doi = {10.1038/s41467-026-73135-8},
url = {https://hal.science/hal-05780978v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Structure of ergosteryl-aspartate synthase reveals how an entrapped tRNA is used like a prosthetic swinging arm in the synthesis of aminoacylated sterols
AU - Hanako Murayama
AU - Nathaniel Yakobov
AU - Nassira Mahmoudi
AU - Sasha Legrosdidier
AU - Nicolas Fournier
AU - Solène Zuttion
AU - Kanata Matsumoto
AU - Michihiro Nishimura
AU - Jingwei Ji
AU - Bruno Senger
AU - Laurence Huck
AU - Howard Gamper
AU - Yoshiaki Kise
AU - Ralph Kleiner
AU - Mathieu Frechin
AU - Ya-Ming Hou
AU - Hubert Becker
AU - Yuzuru Itoh
AU - Frédéric Fischer
AU - Osamu Nureki
PY - 2026
DA - 2026/05/28
JO - Nature Communications
DO - 10.1038/s41467-026-73135-8
UR - https://hal.science/hal-05780978v1
AB - Ergosteryl-3β-O-L-aspartate synthase (ErdS) catalyzes tRNA-dependent aspartylation of ergosterol, a lipid essential for fungal cell membrane integrity. However, the functional significance of ergosteryl-aspartate and the molecular mechanisms underlying its synthesis remain unclear. Here, we show that ErdS localization is highly dynamic and that Erg-Asp is required for proper hyphal growth, sporulation, and spore germination, and likely influences stress tolerance. The cryo-electron microscopy structure of ErdS revealed an unprecedented sterol-binding pocket. In addition, the structures in complex with a non-hydrolyzable Asp-N-tRNAAsp show a tRNA-guided intramolecular aminoacyl transfer mechanism between two functional domains of the enzyme. The CCA end of tRNAAsp undergoes a large displacement to reach the aa-tRNA transfer active site, while the tRNA elbow is clamped by a long extension an N-terminal α-helix. The present structural and mutational analyses demonstrate that domain fusion, dynamic repositioning, and tRNA-mediated substrate handover underlie the multifunctional catalytic efficiency of ErdS and participates in Erg-Asp synthesis independently from protein synthesis. These findings elucidate the regulatory mechanism of tRNA-dependent sterol modification and provide insights into fungal membrane dynamics, highlighting potential targets for antifungal therapies.
SN - 2041-1723
SN - 2041-1723
ER -