Structure and Function of UDP-GalNAc:polypeptide alpha-GalNAc transferases

NIH Pandemic-Era Grants

Pandemic Era Grants

2021

↗ Live URL (may be dead)

Document text

Principal Investigator: Lawrence A. Tabak
Organization: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Fiscal Year: 2021
Award: $957,584
Funding agency: National Institute of Dental and Craniofacial Research

Our lab studies the structure and function of GalNAc-Ts. We published a methods paper in Glycoconjugate J. on mapping O-glycans using solid phase extraction (SPE) enrichment, protease digestion, and Electron-transfer/Higher Energy Collision Dissociation (EThcD) fragmentation. This work utilized O- protease to specifically cleave O-glycosites and studied the influence of negatively charged amino acids and sialic acids on O-glycosite localization.

In collaboration with Drs. Kelly Ten Hagen, Nadine Samara, and Darryl Zeldin, we have submitted a manuscript on the O-glycoylation of the SARS CoV-2 spike protein. We demonstrated that O-glycosylation near the furin cleavage site is mediated by specific members of the GalNAc-T enzyme family and decreases furin cleavage. This O-glycosylation is dependent on the novel proline at position 681 (P681) and mutations at this site in the highly transmissible B.1.1.7 variant abrogate O-glycosylation and increase furin cleavage. These results provide mechanistic insight into the role of the P681 mutation found in the highly transmissible B.1.1.7 variant. A pre-print of this work was deposited into bioRxiv.

In collaboration with Jan Albert Kuivenhoven and colleagues at the University Medical Center of Groningen, in The Netherlands we have explored the role of GalNAc-T2 in whole-body energy homeostasis. Studies in Galnt2-/- mice reveal decreased adiposity, alterations in insulin signaling, and a shift in energy substrate utilization during the day. These findings suggest that the insulin receptor is a novel GalNAc-T2 substrate and may be responsible for local rather than systemic effects. Taken together, our findings identify a novel role for GALNT2 in energy homeostasis.

Terms: <2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><Academic Medical Centers><Acetylgalactosamine><Amino Acids><Autoregulation><B.1.1.7><Biological Function><Biological Process><COVID-19 S protein><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID19 S protein><COVID19 spike glycoprotein><COVID19 spike protein><Charge><Cleaved cell><Collaborations><Core Protein><Deposit><Deposition><Digestion><Dissociation><EC 2.4><Electron Transport><Enzyme Gene><Enzymes><Esteroproteases><Event><Family><GalNAc-T8><GalNAc-transferase><GalNAcT-8><Genetic Alteration><Genetic Change><Genetic defect><Glycoconjugates><Glycoproteins><Glycoside Transferases><Glycosides><Goals><Golgi><Golgi Apparatus><Golgi Complex><Homeostasis><Insulin Receptor><Insulin Receptor Protein-Tyrosine Kinase><Insulin-Dependent Tyrosine Protein Kinase><L-Proline><L-Serine><L-Threonine><Laboratories><Link><Manuscripts><Mediating><Metabolic Glycosylation><Methods><Mice><Mice Mammals><Molecular><Mucins><Mucus Glycoprotein><Murine><Mus><Mutation><N acetylgalactosamine><N-Acetylneuraminic Acids><Netherlands><Obesity><Oligosaccharides><Paper><Peptidases><Peptide Hydrolases><Phase><Physiological Homeostasis><Polypeptide N-acetylgalactosaminyltransferase><Position><Positioning Attribute><Proline><Protease Gene><Proteases><Proteinases><Proteolytic Enzymes><Publishing><Role><SARS-CoV-2 B.1.1.7><SARS-CoV-2 S protein><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2 S protein><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><Serine><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Sialic Acids><Site><Solid><Structure><Threonine><Tn antigen><U.K. variant><UDP-GPAGAT><UDP-GalNAc-polypeptide N-acetylgalactosaminyltransferase><UDP-N-acetylgalactosamine mucin transferase><UDP-N-acetylgalactosamine-polypeptide N-acetylgalactosamine transferase><UDPacetylgalactosamine-protein acetylgalactosaminyltransferase><UK variant><United Kingdom variant><University Medical Centers><Variant><Variation><Work><adiposity><aminoacid><cleaved><coronavirus disease 2019 S protein><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><corpulence><electron transfer><genome mutation><glycosylation><glycosyltransferase><insight><insulin signaling><member><novel><polypeptide><protein-UDPacetylgalactosaminyltransferase><severe acute respiratory syndrome coronavirus 2 B.1.1.7><social role><sugar>