Structural and mechanistic insights into the fungal glycosylphosphatidylinositol mannosyltransferase I complex.

Authors

Jia Liu, Yizheng Yang, Yi Tan, Zhengkang Hua, Xinlin Hu, Xuyang Ding, Ping Yang, Yan Ke, Zhentao Zhang, Tianlu Li, Peng Peng, Min Zhang, Hongjun Yu

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 37. Pages e2617140123. Sep 15, 2026. Epub Sep 10, 2026.

Abstract

Glycosylphosphatidylinositol (GPI) anchoring shapes eukaryotic cell-surface architecture and represents an attractive pathway for antifungal intervention. The first committed mannosylation step in GPI biosynthesis is catalyzed by GPI mannosyltransferase I (GPI-MT-I), a membrane-embedded enzyme complex essential for fungal cell-wall integrity and virulence. Despite its therapeutic potential, the molecular basis and chemical mechanism of this lipid-dependent glycosyltransferase have remained unclear. Here, we combine cryoelectron microscopy, chemical synthesis, and functional analyses to define the architecture, substrate recognition, and catalytic mechanism of fungal GPI-MT-I, the Gpi14-Pbn1 heterodimer. We captured catalytically distinct states of fungal GPI-MT-I, including a ternary complex simultaneously bound to dolichol-phosphate-mannose and GlcN-(acyl)phosphatidylinositol. These reveal a membrane-embedded reaction chamber containing a continuous substrate-binding tunnel, in which two amphipathic lipid substrates are positioned in a head-to-head configuration for glycosyl transfer. Structural and mutational analyses establish GPI-MT-I as a GT-C-fold inverting glycosyltransferase and support a concerted S_N2-like mechanism centered on the conserved catalytic aspartate Asp38. Comparative analyses reveal pronounced fungal-specific structural features with therapeutic potential, explaining the functional incompatibility across species. These findings provide a molecular and chemical blueprint for lipid-linked glycosyl transfer in membranes and a foundation for structure-guided antifungal drug development.

PMID:
42721083
Bibliographic data and abstract were imported from PubMed on 11 Sep 2026.

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