7ZLH

Cryo-EM structure of C-mannosyltransferase CeDPY19, in apo state, bound to CMT2-Fab and anti-Fab nanobody

Summary for 7ZLH

• Entry DOI: 10.2210/pdb7zlh/pdb
• EMDB information: 14780
• Descriptor: CMT2-Fab heavy chain, Anti-Fab nanobody, CMT2-Fab light chain, ... (5 entities in total)
• Functional Keywords: c-mannosyltransferase, membrane protein
• Biological source: synthetic construct; More
• Total number of polymer chains: 4
• Total formula weight: 142522.72

Authors

Bloch, J.S.,Mukherjee, S.,Irobalieva, R.,Kossiakoff, A.A.,Goddard-Borger, E.D.,Locher, K.P. (deposition date: 2022-04-15, release date: 2023-01-11, Last modification date: 2024-11-06)

Primary citation

Bloch, J.S.,John, A.,Mao, R.,Mukherjee, S.,Boilevin, J.,Irobalieva, R.N.,Darbre, T.,Scott, N.E.,Reymond, J.L.,Kossiakoff, A.A.,Goddard-Borger, E.D.,Locher, K.P.
Structure, sequon recognition and mechanism of tryptophan C-mannosyltransferase.
Nat.Chem.Biol., 19:575-584, 2023

PubMed 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.

PubMed: 36604564
DOI: 10.1038/s41589-022-01219-9

Experimental method

ELECTRON MICROSCOPY (2.75 Å)