title: ProteinO-Linked Mannose β-1,4-N-Acetylglucosaminyl-transferase 2 (POMGNT2) Is a Gatekeeper Enzyme for Functional Glycosylation of α-Dystroglycan.
abstract: Disruption of theO-mannosylation pathway involved in functional glycosylation of α-dystroglycan gives rise to congenital muscular dystrophies. ProteinO-linked mannose β-1,4-N-acetylglucosaminyltransferase 2 (POMGNT2) catalyzes the first step toward the functional matriglycan structure on α-dystroglycan that is responsible for binding extracellular matrix proteins and certain arenaviruses. Alternatively, proteinO-linked mannose β-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1) catalyzes the first step toward other various glycan structures present on α-dystroglycan of unknown function. Here, we demonstrate that POMGNT1 is promiscuous forO-mannosylated peptides, whereas POMGNT2 displays significant primary amino acid selectivity near the site ofO-mannosylation. We define a POMGNT2 acceptor motif, conserved among 59 vertebrate species, in α-dystroglycan that when engineered into a POMGNT1-only site is sufficient to convert theO-mannosylated peptide to a substrate for POMGNT2. Additionally, an acceptor glycopeptide is a less efficient substrate for POMGNT2 when two of the conserved amino acids are replaced. These findings begin to define the selectivity of POMGNT2 and suggest that this enzyme functions as a gatekeeper enzyme to prevent the vast majority ofO-mannosylated sites on proteins from becoming modified with glycan structures functional for binding laminin globular domain-containing proteins.
authors.affiliation: From the Complex Carbohydrate Research Center and.|the Departments of Biochemistry and Molecular Biology and.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Halmo
authors.affiliation: From the Complex Carbohydrate Research Center and.|the Departments of Biochemistry and Molecular Biology and.
authors.forename: Danish
authors.initials: D
authors.lastname: Singh
authors.affiliation: From the Complex Carbohydrate Research Center and.
authors.forename: Sneha
authors.initials: S
authors.lastname: Patel
authors.affiliation: From the Complex Carbohydrate Research Center and.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.affiliation: From the Complex Carbohydrate Research Center and.|Chemistry, University of Georgia, Athens, Georgia 30602.
authors.forename: Melanie
authors.initials: M
authors.lastname: Edlin
authors.affiliation: From the Complex Carbohydrate Research Center and.|Chemistry, University of Georgia, Athens, Georgia 30602.
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: Boons
authors.affiliation: From the Complex Carbohydrate Research Center and.|the Departments of Biochemistry and Molecular Biology and.
authors.forename: Kelley W
authors.initials: KW
authors.lastname: Moremen
authors.affiliation: From the Complex Carbohydrate Research Center and.
authors.forename: David
authors.initials: D
authors.lastname: Live
authors.affiliation: From the Complex Carbohydrate Research Center and lwells@ccrc.uga.edu.|the Departments of Biochemistry and Molecular Biology and.
authors.forename: Lance
authors.initials: L
authors.lastname: Wells
mesh_terms: D020134:Catalytic Domain; D049030:Dystroglycans / Q000378:metabolism*; D006031:Glycosylation; D016695:Glycosyltransferases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008358:Mannose / Q000378:metabolism
chemical_list: D049030:Dystroglycans; D016695:Glycosyltransferases; C576562:POMGNT2 protein, human; D008358:Mannose
keywords: dystroglycan; enzyme kinetics; glycobiology; glycoprotein; glycosyltransferase