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Structural characterisation of the fungal Pmt4 homodimer

Protein O-mannosyltransferases (PMTs) are conserved endoplasmic reticulum membrane-embedded enzymes responsible for the transfer of mannose from dolichol phosphate-mannose (Dol-P-Man) to serine/threonine-rich protein substrates or unfolded proteins. PMTs from three subfamilies form obligate dimers w...

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Main Authors: McDowell, Melanie (Author) , Wild, Klemens (Author) , Fiorentino, Francesco (Author) , Bausewein, Daniela (Author) , Metschies, Anke (Author) , Chiapparino, Antonella (Author) , Hackmann, Yvonne (Author) , Bilsing, Florestan (Author) , Brenske, David (Author) , Mortensen, Sofia (Author) , Wu, Di (Author) , Robinson, Carol V. (Author) , Strahl, Sabine (Author) , Sinning, Irmgard (Author)
Format: Article (Journal)
Language:English
Published: 14 December 2025
In: Nature Communications
Year: 2025, Volume: 16, Pages: 1-14
ISSN:2041-1723
DOI:10.1038/s41467-025-67412-1
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-025-67412-1
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-025-67412-1
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Author Notes:Melanie A. McDowell, Klemens Wild, Francesco Fiorentino, Daniela Bausewein, Anke Metschies, Antonella Chiapparino, Yvonne Hackmann, Florestan L. Bilsing, David Brenske, Sofia Mortensen, Di Wu, Carol V. Robinson, Sabine Strahl & Irmgard Sinning

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520 |a Protein O-mannosyltransferases (PMTs) are conserved endoplasmic reticulum membrane-embedded enzymes responsible for the transfer of mannose from dolichol phosphate-mannose (Dol-P-Man) to serine/threonine-rich protein substrates or unfolded proteins. PMTs from three subfamilies form obligate dimers with different substrate specificities and require the concerted action of their transmembrane domains (TMDs) and a luminal MIR domain for catalysis. Here, we present structures, native mass spectrometry, and structure-based mutagenesis of the fungal Pmt4 homodimer. The core fold of the TMDs and MIR domain is conserved with the Pmt1-Pmt2 heterodimer, indicating a shared catalytic mechanism. Distinct from Pmt4, the MIR domain interacts in cis with the TMDs of the same subunit and has a β-hairpin insertion required for O-mannosylation of substrates. We further identify a cytosolic binding site for substrate Dol-P-Man within the Pmt4 TMDs, which is conserved amongst PMTs and important for in vivo activity. Thus, we provide a framework to understand the substrate specificity and regulation of the Pmt4 homodimer. 
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