Our paper Structure, sequon recognition and mechanism of tryptophan C-mannosyltransferase is published in 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.

Author(s):
Joël S. Bloch, Alan John, Runyu Mao, Somnath Mukherjee, Jérémy Boilevin, Rossitza N. Irobalieva, Tamis Darbre, Nichollas E. Scott, Jean-Louis Reymond, Anthony A. Kossiakoff, Ethan D. Goddard-Borger and Kaspar P. Locher