Bloch, Joël S; John, Alan; Mao, Runyu; Mukherjee, Somnath; Boilevin, Jérémy; Irobalieva, Rossitza N; Darbre, Tamis; Scott, Nichollas E; Reymond, Jean-Louis; Kossiakoff, Anthony A; Goddard-Borger, Ethan D; Locher, Kaspar P (2023). Structure, sequon recognition and mechanism of tryptophan C-mannosyltransferase. Nature chemical biology, 19(5), pp. 575-584. Springer Nature 10.1038/s41589-022-01219-9
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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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP) |
UniBE Contributor: |
Boilevin, Jérémy Mathias, Darbre, Tamis, Reymond, Jean-Louis |
Subjects: |
500 Science > 570 Life sciences; biology 500 Science > 540 Chemistry 600 Technology > 610 Medicine & health |
ISSN: |
1552-4469 |
Publisher: |
Springer Nature |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
06 Jan 2023 10:55 |
Last Modified: |
04 May 2023 00:13 |
Publisher DOI: |
10.1038/s41589-022-01219-9 |
PubMed ID: |
36604564 |
BORIS DOI: |
10.48350/176941 |
URI: |
https://boris.unibe.ch/id/eprint/176941 |
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