Title : Discovery of an O-mannosylation pathway selectively serving cadherins and
protocadherins
Abstract :
- The cadherin ( cdh ) superfamily of adhesion molecules carry O-linked mannose (O-Man) glycans at highly conserved sites localized to specific β-strands of their extracellular cdh ( EC ) domains
- These O-Man glycans do not appear to be elongated like O-Man glycans found on α-dystroglycan (α-DG), and we recently demonstrated that initiation of cdh/protocadherin (pcdh) O-Man glycosylation is not dependent on the evolutionary conserved POMT1 / POMT2 enzymes that initiate O-Man glycosylation on α-DG
- Here, we used a CRISPR/Cas9 genetic dissection strategy combined with sensitive and quantitative O-Man glycoproteomics to identify a homologous family of four putative protein O-mannosyltransferases encoded by the TMTC1-4 genes, which were found to be imperative for cdh and p cdh O-Man glycosylation
- KO of all four TMTC genes in HEK293 cells resulted in specific loss of cdh and pcdh O-Man glycosylation, whereas combined KO of TMTC1 and TMTC3 resulted in selective loss of O-Man glycans on specific β-strands of EC domains , suggesting that each isoenzyme serves a different function
- In addition, O-Man glycosylation of IPT /TIG domains of plexins and hepatocyte growth factor receptor was not affected in TMTC KO cells, suggesting the existence of yet another O-Man glycosylation machinery
- Our study demonstrates that regulation of O-mannosylation in higher eukaryotes is more complex than envisioned, and the discovery of the functions of TMTCs provide insight into cobblestone lissencephaly caused by deficiency in TMTC3
Output (sent_index, trigger,
protein,
sugar,
site):
- 5. domains, , -, O-Man glycosylation, domains
- 5. glycosylation, , hepatocyte growth factor receptor, -, domains
Output(Part-Of) (sent_index,
protein,
site):
- 1. EC, domains
- 1. cdh, domains
- 4. EC, domains
- 5. IPT, domains
- 5. hepatocyte growth factor receptor, domains
*Output_Site_Fusion* (sent_index,
protein,
sugar,
site):