Structure, sequon recognition and mechanism of tryptophan C-mannosyltransferase.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
05 2023
05 2023
Historique:
received:
22
06
2022
accepted:
28
10
2022
medline:
4
5
2023
pubmed:
6
1
2023
entrez:
5
1
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36604564
doi: 10.1038/s41589-022-01219-9
pii: 10.1038/s41589-022-01219-9
pmc: PMC10154233
doi:
Substances chimiques
Mannosyltransferases
EC 2.4.1.-
Tryptophan
8DUH1N11BX
Peptides
0
Membrane Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
575-584Informations de copyright
© 2023. The Author(s).
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