Structure, sequon recognition and mechanism of tryptophan C-mannosyltransferase
- Author(s)
- 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;
- Details
- Publication Year 2023-01-05,Volume 19,Issue #5,Page 575-584
- Journal Title
- Nature Chemical Biology
- Abstract
- 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.
- Publisher
- NPG
- Keywords
- Humans; Mannosyltransferases/genetics/chemistry/metabolism; Tryptophan/metabolism; Glycosylation; Peptides/metabolism; Membrane Proteins/metabolism
- Research Division(s)
- Chemical Biology
- PubMed ID
- 36604564
- Publisher's Version
- https://doi.org/10.1038/s41589-022-01219-9
- Open Access at Publisher's Site
https://doi.org/10.1038/s41589-022-01219-9- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-03-17 11:09:06
Last Modified: 2023-06-13 01:17:46