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Cryo-EM structure of C-mannosyltransferase CeDPY19, in apo state, bound to CMT2-Fab and anti-Fab nanobodyCryo-EM structure of C-mannosyltransferase CeDPY19, in apo state, bound to CMT2-Fab and anti-Fab nanobody
Structural highlights
FunctionDPY19_CAEEL C-mannosyltransferase that mediates C-mannosylation of tryptophan residues on target proteins such as unc-5 and mig-21. Mediates the attachment of alpha-mannose in C-C linkage to the C2 of the indole ring of tryptophan. C-mannosylation takes place in the endoplasmic reticulum and frequently found in thrombospondin (TSP) type-1 repeats and in the WSXWS motif of type I cytokine receptors. Required to orient neuroblasts QL and QR correctly on the anterior/posterior (A/P) axis: QL and QR are born in the same A/P position, but polarize and migrate left/right asymmetrically, QL migrates toward the posterior and QR migrates toward the anterior. Required with unc-40 to express mab-5 correctly in the Q cell descendants.[1] [2] Publication Abstract from PubMedC-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. Structure, sequon recognition and mechanism of tryptophan C-mannosyltransferase.,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 Nat Chem Biol. 2023 May;19(5):575-584. doi: 10.1038/s41589-022-01219-9. Epub 2023 , Jan 5. PMID:36604564[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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