Revealing the structure of a sugar-transferring enzyme associated with colorectal cancer
The layer of mucus that lines the gastrointestinal tract protects the underlying organs from infection, as well as physical and chemical damage. It contains mucin proteins that are heavily modified with sugar molecules via a process called O-glycosylation. An enzyme called polypeptide N-acetylgalactosaminyl transferase 12 (GalNAc-T12), which assists with O-glycosylation, has been found to be mutated in colorectal cancer patients, but the molecular details by which it works and its contribution to gastrointestinal health has not been studied.
Using X-ray crystallography, IRP researchers led by Laurence Tabak, D.D.S., Ph.D., and Nadine Samara, Ph.D., revealed the structure of GalNAc-T12, including its active site, where the process of O-glycosylation occurs. They also discovered that the structure of the enzyme’s active site is disrupted by mutations found in colorectal cancer patients, thereby preventing necessary O-glycosylation.
This research reveals important information about the precise mechanism by which GalNAc-T12 causes O-glycosylation. Greater insight into this process can further our understanding of how the enzyme and the specific molecules it acts on work and how they might contribute to cancer initiation and progression.
Fernandez AJ, Daniel EJP, Mahajan SP, Gray JJ, Gerken TA, Tabak LA, Samara NL. (2019). The structure of the colorectal cancer-associated enzyme GalNAc-T12 reveals how nonconserved residues dictate its function. PNAS. Oct 8;116(41):20404-20410.