| Structural highlights
Disease
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
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.[2] [3] [4] [5] 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.[6] [7] [8] [9] 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.[10] [11] [12] [13]
Publication Abstract from PubMed
We have carried out a comparative study of the conformational impact of modifications to threonine residues of either alpha-O-Man or alpha-O-GalNAc in the context of a sequence from the mucin-like region of alpha-dystroglycan. Both such modifications can coexist in this domain of the glycoprotein. Solution NMR experiments and molecular dynamics calculations were employed. Comparing the results for an unmodified peptide Ac- PPTTTTKKP-NH2 sequence from alpha-dystroglycan, and glycoconjugates with either modification on the Ts, we find that the impact of the alpha-O-Man modification on the peptide scaffold is quite limited, while that of the alpha-O-GalNAc is more profound. The results for the alpha-O-GalNAc glycoconjugate are consistent with what has been seen earlier in other systems. Further examination of the NMR-based structure and the MD results suggest a more extensive network of hydrogen bond interactions within the alpha-O-GalNAc-threonine residue than has been previously appreciated, which influences the properties of the protein backbone. The conformational effects are relevant to the mechanical properties of alpha-dystroglycan.
Contrasting the conformational effects of alpha-O-GalNAc and alpha-O-Man glycan protein modifications and their impact on the mucin-like region of alpha-dystroglycan.,Borgert A, Foley BL, Live D Glycobiology. 2021 Jun 3;31(5):649-661. doi: 10.1093/glycob/cwaa112. PMID:33295623[14]
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
- ↑ 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
- ↑ Borgert A, Foley BL, Live D. Contrasting the conformational effects of alpha-O-GalNAc and alpha-O-Man glycan protein modifications and their impact on the mucin-like region of alpha-dystroglycan. Glycobiology. 2021 Jun 3;31(5):649-661. doi: 10.1093/glycob/cwaa112. PMID:33295623 doi:http://dx.doi.org/10.1093/glycob/cwaa112
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