title: DistinctC-mannosylation of netrin receptor thrombospondin type 1 repeats by mammalian DPY19L1 and DPY19L3.
abstract: Thrombospondin type 1 repeats (TSRs) occur in diverse proteins involved in adhesion and signaling. The two extracellular TSRs of the netrin receptor UNC5A contain WxxWxxWxxC motifs that can beC-mannosylated on all tryptophans. A singleC-mannosyltransferase (dumpy-19, DPY-19), modifying the first two tryptophans, occurs inCaenorhabditis elegans, but four putative enzymes (DPY-19-like 1-4, DPY19L1-4) exist in mammals. Single and triple CRISPR-Cas9 knockouts of the three homologs that are expressed in Chinese hamster ovary cells (DPY19L1, DPY19L3, and DPY19L4) and complementation experiments with mouse homologs showed that DPY19L1 preferentially mannosylates the first two tryptophans and DPY19L3 prefers the third, whereas DPY19L4 has no function in TSR glycosylation. Mannosylation by DPY19L1 but not DPY19L3 is required for transport of UNC5A from the endoplasmic reticulum to the cell surface. In vertebrates, a newC-mannosyltransferase has apparently evolved to increase glycosylation of TSRs, potentially to increase the stability of the structurally essential tryptophan ladder or to provide additional adhesion functions.
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Shcherbakova
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Tiemann
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Falk F R
authors.initials: FF
authors.lastname: Buettner
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, 30625 Hannover, Germany bakker.hans@mh-hannover.de.
authors.forename: Hans
authors.initials: H
authors.lastname: Bakker
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D016466:CHO Cells; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D002448:Cell Adhesion / Q000235:genetics*; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D008358:Mannose / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D000075386:Netrin Receptors / Q000235:genetics / Q000378:metabolism*; D020449:Repetitive Sequences, Amino Acid / Q000235:genetics; D019700:Thrombospondin 1 / Q000235:genetics
chemical_list: D018955:CD36 Antigens; D029742:Caenorhabditis elegans Proteins; C417031:DPY-19 protein, C elegans; C568704:Dpy19l1 protein, mouse; D008565:Membrane Proteins; D000075386:Netrin Receptors; D019700:Thrombospondin 1; C000617308:Unc5A protein, mouse; D008358:Mannose
keywords: C-mannosylation; glycosylation; thrombospondin type 1 repeat