6xi2
Apo form of POMGNT2
Structural highlights
DiseasePMGT2_HUMAN Walker-Warburg syndrome. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionPMGT2_HUMAN 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.[1] [2] Publication Abstract from PubMedThe canonical O-mannosylation pathway in humans is essential for the functional glycosylation of alpha-dystroglycan. Disruption of this post-translational modification pathway leads to congenital muscular dystrophies. The first committed step in the construction of a functional matriglycan structure involves the post-translational modification of alpha-dystroglycan. This is essential for binding extracellular matrix proteins and arenaviruses, and is catalyzed by beta-1,4-N-acetylglucosaminyltransferase 2 (POMGNT2). While another glycosyl transferase, beta-1,4-N-acetylglucosaminyltransferase 1 (POMGNT1), has been shown to be promiscuous in extending O-mannosylated sites, POMGNT2 has been shown to display significant primary amino-acid selectivity near the site of O-mannosylation. Moreover, several single point mutations in POMGNT2 have been identified in patients with assorted dystroglycanopathies such as Walker-Warburg syndrome and limb girdle muscular dystrophy. To gain insight into POMGNT2 function in humans, the enzyme was expressed as a soluble, secreted fusion protein by transient infection of HEK293 suspension cultures. Here, crystal structures of POMGNT2 (amino-acid residues 25-580) with and without UDP bound are reported. Consistent with a novel fold and a unique domain organization, no molecular-replacement model was available and phases were obtained through crystallization of a selenomethionine variant of the enzyme in the same space group. Tetragonal (space group P4212; unit-cell parameters a = b = 129.8, c = 81.6 A, alpha = gamma = beta = 90 degrees ) crystals with UDP bound diffracted to 1.98 A resolution and contained a single monomer in the asymmetric unit. Orthorhombic (space group P212121; unit-cell parameters a = 142.3, b = 153.9, c = 187.4 A, alpha = gamma = beta = 90 degrees ) crystals were also obtained; they diffracted to 2.57 A resolution and contained four monomers with differential glycosylation patterns and conformations. These structures provide the first rational basis for an explanation of the loss-of-function mutations and offer significant insights into the mechanics of this important human enzyme. Crystal structures of beta-1,4-N-acetylglucosaminyltransferase 2: structural basis for inherited muscular dystrophies.,Yang JY, Halmo SM, Praissman J, Chapla D, Singh D, Wells L, Moremen KW, Lanzilotta WN Acta Crystallogr D Struct Biol. 2021 Apr 1;77(Pt 4):486-495. doi:, 10.1107/S2059798321001261. Epub 2021 Mar 30. PMID:33825709[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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