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Publication Abstract from PubMed

C-linked glycosylation is essential for the trafficking, folding and function of secretory and transmembrane proteins involved in cellular communication processes. The tryptophan C-mannosyltransferase (CMT) enzymes that install the modification attach a mannose to the first tryptophan of WxxW/C sequons in nascent polypeptide chains by an unknown mechanism. Here, we report cryogenic-electron microscopy structures of Caenorhabditis elegans CMT in four key states: apo, acceptor peptide-bound, donor-substrate analog-bound and as a trapped ternary complex with both peptide and a donor-substrate mimic bound. The structures indicate how the C-mannosylation sequon is recognized by this CMT and its paralogs, and how sequon binding triggers conformational activation of the donor substrate: a process relevant to all glycosyltransferase C superfamily enzymes. Our structural data further indicate that the CMTs adopt an unprecedented electrophilic aromatic substitution mechanism to enable the C-glycosylation of proteins. These results afford opportunities for understanding human disease and therapeutic targeting of specific CMT paralogs.

Structure, sequon recognition and mechanism of tryptophan C-mannosyltransferase.,Bloch JS, John A, Mao R, Mukherjee S, Boilevin J, Irobalieva RN, Darbre T, Scott NE, Reymond JL, Kossiakoff AA, Goddard-Borger ED, Locher KP Nat Chem Biol. 2023 May;19(5):575-584. doi: 10.1038/s41589-022-01219-9. Epub 2023 , Jan 5. PMID:36604564^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.