Structure and mechanism of cancer-associated N-acetylglucosaminyltransferase-V.

ABSTRACT: N-acetylglucosaminyltransferase-V (GnT-V) alters the structure of specific N-glycans by modifying ?1-6-linked mannose with a ?1-6-linked N-acetylglucosamine branch. ?1-6 branch formation on cell surface receptors accelerates cancer metastasis, making GnT-V a promising target for drug development. However, the molecular basis of GnT-V's catalytic mechanism and substrate specificity are not fully understood. Here, we report crystal structures of human GnT-V luminal domain with a substrate analog. GnT-V luminal domain is composed of a GT-B fold and two accessary domains. Interestingly, two aromatic rings sandwich the ?1-6 branch of the acceptor N-glycan and restrain the global conformation, partly explaining the fine branch specificity of GnT-V. In addition, interaction of the substrate N-glycoprotein with GnT-V likely contributes to protein-selective and site-specific glycan modification. In summary, the acceptor-GnT-V complex structure suggests a catalytic mechanism, explains the previously observed inhibition of GnT-V by branching enzyme GnT-III, and provides a basis for the rational design of drugs targeting N-glycan branching.

SUBMITTER: Nagae M 

PROVIDER: S-EPMC6107550 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature