| Structural highlights
5ggp is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Related: | 5ggf, 5ggg, 5ggi, 5ggj, 5ggk, 5ggl, 5ggn, 5ggo |
| Gene: | POMGNT1, MGAT1.2, UNQ746/PRO1475 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[PMGT1_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. [DAG1_HUMAN] Defects in DAG1 are the cause of muscular dystrophy-dystroglycanopathy limb-girdle type C7 (MDDGC7) [MIM:613818]. An autosomal recessive muscular dystrophy showing onset in early childhood, and associated with mental retardation without structural brain anomalies. Note=MDDGC7 is caused by DAG1 mutations that interfere with normal post-translational processing, resulting in defective DAG1 glycosylation and impaired interactions with extracellular-matrix components. Other muscular dystrophy-dystroglycanopathies are caused by defects in enzymes involved in protein O-glycosylation.[1]
Function
[PMGT1_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.[2] [DAG1_HUMAN] The dystroglycan complex is involved in a number of processes including laminin and basement membrane assembly, sarcolemmal stability, cell survival, peripheral nerve myelination, nodal structure, cell migration, and epithelial polarization.[3] [4] [5] [6] Alpha-dystroglycan is an extracellular peripheral glycoprotein that acts as a receptor for both extracellular matrix proteins containing laminin-G domains, and for certain adenoviruses. Receptor for laminin-2 (LAMA2) and agrin in peripheral nerve Schwann cells. Also acts as a receptor for M.leprae in peripheral nerve Schwann cells but only in the presence of the G-domain of LAMA2, and for lymphocytic choriomeningitis virus, Old World Lassa fever virus, and clade C New World arenaviruses.[7] [8] [9] [10] Beta-dystroglycan is a transmembrane protein that plays important roles in connecting the extracellular matrix to the cytoskeleton. Acts as a cell adhesion receptor in both muscle and non-muscle tissues. Receptor for both DMD and UTRN and, through these interactions, scaffolds axin to the cytoskeleton. Also functions in cell adhesion-mediated signaling and implicated in cell polarity.[11] [12] [13] [14]
Publication Abstract from PubMed
The 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[15]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hara Y, Balci-Hayta B, Yoshida-Moriguchi T, Kanagawa M, Beltran-Valero de Bernabe D, Gundesli H, Willer T, Satz JS, Crawford RW, Burden SJ, Kunz S, Oldstone MB, Accardi A, Talim B, Muntoni F, Topaloglu H, Dincer P, Campbell KP. A dystroglycan mutation associated with limb-girdle muscular dystrophy. N Engl J Med. 2011 Mar 10;364(10):939-46. doi: 10.1056/NEJMoa1006939. PMID:21388311 doi:10.1056/NEJMoa1006939
- ↑ Yoshida A, Kobayashi K, Manya H, Taniguchi K, Kano H, Mizuno M, Inazu T, Mitsuhashi H, Takahashi S, Takeuchi M, Herrmann R, Straub V, Talim B, Voit T, Topaloglu H, Toda T, Endo T. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev Cell. 2001 Nov;1(5):717-24. PMID:11709191
- ↑ Rambukkana A, Yamada H, Zanazzi G, Mathus T, Salzer JL, Yurchenco PD, Campbell KP, Fischetti VA. Role of alpha-dystroglycan as a Schwann cell receptor for Mycobacterium leprae. Science. 1998 Dec 11;282(5396):2076-9. PMID:9851927
- ↑ Sotgia F, Lee H, Bedford MT, Petrucci T, Sudol M, Lisanti MP. Tyrosine phosphorylation of beta-dystroglycan at its WW domain binding motif, PPxY, recruits SH2 domain containing proteins. Biochemistry. 2001 Dec 4;40(48):14585-92. PMID:11724572
- ↑ Imperiali M, Thoma C, Pavoni E, Brancaccio A, Callewaert N, Oxenius A. O Mannosylation of alpha-dystroglycan is essential for lymphocytic choriomeningitis virus receptor function. J Virol. 2005 Nov;79(22):14297-308. PMID:16254364 doi:10.1128/JVI.79.22.14297-14308.2005
- ↑ Rojek JM, Spiropoulou CF, Campbell KP, Kunz S. Old World and clade C New World arenaviruses mimic the molecular mechanism of receptor recognition used by alpha-dystroglycan's host-derived ligands. J Virol. 2007 Jun;81(11):5685-95. Epub 2007 Mar 14. PMID:17360738 doi:10.1128/JVI.02574-06
- ↑ Rambukkana A, Yamada H, Zanazzi G, Mathus T, Salzer JL, Yurchenco PD, Campbell KP, Fischetti VA. Role of alpha-dystroglycan as a Schwann cell receptor for Mycobacterium leprae. Science. 1998 Dec 11;282(5396):2076-9. PMID:9851927
- ↑ Sotgia F, Lee H, Bedford MT, Petrucci T, Sudol M, Lisanti MP. Tyrosine phosphorylation of beta-dystroglycan at its WW domain binding motif, PPxY, recruits SH2 domain containing proteins. Biochemistry. 2001 Dec 4;40(48):14585-92. PMID:11724572
- ↑ Imperiali M, Thoma C, Pavoni E, Brancaccio A, Callewaert N, Oxenius A. O Mannosylation of alpha-dystroglycan is essential for lymphocytic choriomeningitis virus receptor function. J Virol. 2005 Nov;79(22):14297-308. PMID:16254364 doi:10.1128/JVI.79.22.14297-14308.2005
- ↑ Rojek JM, Spiropoulou CF, Campbell KP, Kunz S. Old World and clade C New World arenaviruses mimic the molecular mechanism of receptor recognition used by alpha-dystroglycan's host-derived ligands. J Virol. 2007 Jun;81(11):5685-95. Epub 2007 Mar 14. PMID:17360738 doi:10.1128/JVI.02574-06
- ↑ Rambukkana A, Yamada H, Zanazzi G, Mathus T, Salzer JL, Yurchenco PD, Campbell KP, Fischetti VA. Role of alpha-dystroglycan as a Schwann cell receptor for Mycobacterium leprae. Science. 1998 Dec 11;282(5396):2076-9. PMID:9851927
- ↑ Sotgia F, Lee H, Bedford MT, Petrucci T, Sudol M, Lisanti MP. Tyrosine phosphorylation of beta-dystroglycan at its WW domain binding motif, PPxY, recruits SH2 domain containing proteins. Biochemistry. 2001 Dec 4;40(48):14585-92. PMID:11724572
- ↑ Imperiali M, Thoma C, Pavoni E, Brancaccio A, Callewaert N, Oxenius A. O Mannosylation of alpha-dystroglycan is essential for lymphocytic choriomeningitis virus receptor function. J Virol. 2005 Nov;79(22):14297-308. PMID:16254364 doi:10.1128/JVI.79.22.14297-14308.2005
- ↑ Rojek JM, Spiropoulou CF, Campbell KP, Kunz S. Old World and clade C New World arenaviruses mimic the molecular mechanism of receptor recognition used by alpha-dystroglycan's host-derived ligands. J Virol. 2007 Jun;81(11):5685-95. Epub 2007 Mar 14. PMID:17360738 doi:10.1128/JVI.02574-06
- ↑ 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. Carbohydrate-binding domain of the POMGnT1 stem region modulates O-mannosylation sites of alpha-dystroglycan. 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 doi:http://dx.doi.org/10.1073/pnas.1525545113
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