Research Structural characterisation of the fungal Pmt4 homodimer
Insights into substrate specificity and regulation of Pmt4
Protein O-mannosylation is an evolutionarily conserved and essential post-translational modification. Protein-O-mannosyltransferases (PMTs) are ER membrane-embedded enzymes responsible for the transfer of mannose from dolichol phosphate-mannose (Dol-P-Man) to unfolded proteins or serine/threonine-rich protein substrates. In yeast, unfolded protein O-mannosylation (UPOM) is important for ER protein quality control, while in humans impairment of O-mannosylation leads to severe diseases.
Pmt4 provides a powerful model for understanding congenital muscular dystrophies in humans linked to reduced O-mannosylation of α-dystroglycan (αDG) by POMT1-POMT2, as Pmt4 mannosylates αDG-derived peptides and is catalytically impaired by the insertion of pathogenic POMT1 mutations. In a collaborative effort, the groups of Irmgard Sinning (BZH), Sabine Strahl (COS) and Carol Robinson (Oxford, UK) combined cryo-EM and X-ray structure determination, native mass spectrometry, and in vivo functional assays to obtain mechanistic insights into the fungal Pmt4 homodimer. Their work substantially advances the understanding of the substrate specificity and regulation of the Pmt4 homodimer.
