5ggo
From Proteopedia
Crystal structure of N-terminal domain of human protein O-mannose beta-1,2-N-acetylglucosaminyltransferase in complex with GalNac-beta1,3-GlcNAc-beta-pNP
Structural highlights
DiseasePMGT1_HUMAN Walker-Warburg syndrome;Autosomal recessive limb-girdle muscular dystrophy type 2O;Congenital muscular dystrophy with cerebellar involvement;Muscle-eye-brain disease. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionPMGT1_HUMAN Participates in O-mannosyl glycosylation. May be responsible for the synthesis of the GlcNAc(beta1-2)Man(alpha1-)O-Ser/Thr moiety on alpha-dystroglycan and other O-mannosylated proteins. Is specific for alpha linked terminal mannose and does not have MGAT3, MGAT4, MGAT5, MGAT7 or MGAT8 activity.[1] Publication Abstract from PubMedThe dystrophin glycoprotein complex, which connects the cell membrane to the basement membrane, is essential for a variety of biological events, including maintenance of muscle integrity. An O-mannose-type GalNAc-beta1,3-GlcNAc-beta1,4-(phosphate-6)-Man structure of alpha-dystroglycan (alpha-DG), a subunit of the complex that is anchored to the cell membrane, interacts directly with laminin in the basement membrane. Reduced glycosylation of alpha-DG is linked to some types of inherited muscular dystrophy; consistent with this relationship, many disease-related mutations have been detected in genes involved in O-mannosyl glycan synthesis. Defects in protein O-linked mannose beta1,2-N-acetylglucosaminyltransferase 1 (POMGnT1), a glycosyltransferase that participates in the formation of GlcNAc-beta1,2-Man glycan, are causally related to muscle-eye-brain disease (MEB), a congenital muscular dystrophy, although the role of POMGnT1 in postphosphoryl modification of GalNAc-beta1,3-GlcNAc-beta1,4-(phosphate-6)-Man glycan remains elusive. Our crystal structures of POMGnT1 agreed with our previous results showing that the catalytic domain recognizes substrate O-mannosylated proteins via hydrophobic interactions with little sequence specificity. Unexpectedly, we found that the stem domain recognizes the beta-linked GlcNAc of O-mannosyl glycan, an enzymatic product of POMGnT1. This interaction may recruit POMGnT1 to a specific site of alpha-DG to promote GlcNAc-beta1,2-Man clustering and also may recruit other enzymes that interact with POMGnT1, e.g., fukutin, which is required for further modification of the GalNAc-beta1,3-GlcNAc-beta1,4-(phosphate-6)-Man glycan. On the basis of our findings, we propose a mechanism for the deficiency in postphosphoryl modification of the glycan observed in POMGnT1-KO mice and MEB patients. Carbohydrate-binding domain of the POMGnT1 stem region modulates O-mannosylation sites of alpha-dystroglycan.,Kuwabara N, Manya H, Yamada T, Tateno H, Kanagawa M, Kobayashi K, Akasaka-Manya K, Hirose Y, Mizuno M, Ikeguchi M, Toda T, Hirabayashi J, Senda T, Endo T, Kato R Proc Natl Acad Sci U S A. 2016 Aug 16;113(33):9280-5. doi:, 10.1073/pnas.1525545113. Epub 2016 Aug 4. PMID:27493216[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
