7e9j | pdb_00007e9j
Crystal Structure of POMGNT2 in complex with UDP
Structural highlights
Function[PMGT2_BOVIN] O-linked mannose beta-1,4-N-acetylglucosaminyltransferase that transfers UDP-N-acetyl-D-glucosamine to the 4-position of the mannose to generate N-acetyl-D-glucosamine-beta-1,4-O-D-mannosylprotein. Involved in the biosynthesis of the phosphorylated O-mannosyl trisaccharide (N-acetylgalactosamine-beta-3-N-acetylglucosamine-beta-4-(phosphate-6-)mannose), a carbohydrate structure present in alpha-dystroglycan (DAG1), which is required for binding laminin G-like domain-containing extracellular proteins with high affinity (By similarity).[UniProtKB:Q8NAT1] Publication Abstract from PubMedDefects in the O-mannosyl glycan of alpha-dystroglycan (alpha-DG) are associated with alpha-dystroglycanopathy, a group of congenital muscular dystrophies. While alpha-DG has many O-mannosylation sites, only the specific positions can be modified with the functional O-mannosyl glycan, namely, core M3-type glycan. POMGNT2 is a glycosyltransferase which adds beta1,4-linked GlcNAc to the O-mannose (Man) residue to acquire core M3-type glycan. Although it is assumed that POMGNT2 extends the specific O-Man residues around particular amino acid sequences, the details are not well understood. Here, we determined a series of crystal structures of POMGNT2 with and without the acceptor O-mannosyl peptides and identified the critical interactions between POMGNT2 and the acceptor peptide. POMGNT2 has an N-terminal catalytic domain and a C-terminal fibronectin type III (FnIII) domain, and forms a dimer. The acceptor peptide is sandwiched between the two protomers. The catalytic domain of one protomer recognizes the O-mannosylation site (TPT motif), and the FnIII domain of the other protomer recognizes the C-terminal region of the peptide. Structure-based mutational studies confirmed that amino acid residues of the catalytic domain interacting with mannose or the TPT motif are essential for POMGNT2 enzymatic activity. In addition, the FnIII domain is also essential for the activity and it interacts with the peptide mainly by hydrophobic interaction. Our study provides the first atomic-resolution insights into specific acceptor recognition by the FnIII domain of POMGNT2. The catalytic mechanism of POMGNT2 is proposed based on the structure. The structure of POMGNT2 provides new insights into the mechanism to determine the functional O-mannosylation site on alpha-dystroglycan.,Imae R, Kuwabara N, Manya H, Tanaka T, Tsuyuguchi M, Mizuno M, Endo T, Kato R Genes Cells. 2021 Apr 23. doi: 10.1111/gtc.12853. PMID:33893702[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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