| 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] [DMD_HUMAN] Defects in DMD are the cause of Duchenne muscular dystrophy (DMD) [MIM:310200]. DMD is the most common form of muscular dystrophy; a sex-linked recessive disorder. It typically presents in boys aged 3 to 7 year as proximal muscle weakness causing waddling gait, toe-walking, lordosis, frequent falls, and difficulty in standing up and climbing up stairs. The pelvic girdle is affected first, then the shoulder girdle. Progression is steady and most patients are confined to a wheelchair by age of 10 or 12. Flexion contractures and scoliosis ultimately occur. About 50% of patients have a lower IQ than their genetic expectations would suggest. There is no treatment.[2] [3] [4] [5] Defects in DMD are the cause of Becker muscular dystrophy (BMD) [MIM:300376]. BMD resembles DMD in hereditary and clinical features but is later in onset and more benign.[6] Defects in DMD are a cause of cardiomyopathy dilated X-linked type 3B (CMD3B) [MIM:302045]; also known as X-linked dilated cardiomyopathy (XLCM). Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.[7] [8] [9]
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.[10] [11] [12] [13] 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.[14] [15] [16] [17] 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.[18] [19] [20] [21] [DMD_HUMAN] Anchors the extracellular matrix to the cytoskeleton via F-actin. Ligand for dystroglycan. Component of the dystrophin-associated glycoprotein complex which accumulates at the neuromuscular junction (NMJ) and at a variety of synapses in the peripheral and central nervous systems and has a structural function in stabilizing the sarcolemma. Also implicated in signaling events and synaptic transmission.[22]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Dystrophin and beta-dystroglycan are components of the dystrophin-glycoprotein complex (DGC), a multimolecular assembly that spans the cell membrane and links the actin cytoskeleton to the extracellular basal lamina. Defects in the dystrophin gene are the cause of Duchenne and Becker muscular dystrophies. The C-terminal region of dystrophin binds the cytoplasmic tail of beta-dystroglycan, in part through the interaction of its WW domain with a proline-rich motif in the tail of beta-dystroglycan. Here we report the crystal structure of this portion of dystrophin in complex with the proline-rich binding site in beta-dystroglycan. The structure shows that the dystrophin WW domain is embedded in an adjacent helical region that contains two EF-hand-like domains. The beta-dystroglycan peptide binds a composite surface formed by the WW domain and one of these EF-hands. Additionally, the structure reveals striking similarities in the mechanisms of proline recognition employed by WW domains and SH3 domains.
Structure of a WW domain containing fragment of dystrophin in complex with beta-dystroglycan.,Huang X, Poy F, Zhang R, Joachimiak A, Sudol M, Eck MJ Nat Struct Biol. 2000 Aug;7(8):634-8. PMID:10932245[23]
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
- ↑ Prior TW, Papp AC, Snyder PJ, Burghes AH, Bartolo C, Sedra MS, Western LM, Mendell JR. A missense mutation in the dystrophin gene in a Duchenne muscular dystrophy patient. Nat Genet. 1993 Aug;4(4):357-60. PMID:8401582 doi:http://dx.doi.org/10.1038/ng0893-357
- ↑ Prior TW, Bartolo C, Papp AC, Snyder PJ, Sedra MS, Burghes AH, Mendell JR. Identification of a missense mutation, single base deletion and a polymorphism in the dystrophin exon 16. Hum Mol Genet. 1994 Jul;3(7):1173-4. PMID:7981690
- ↑ Lenk U, Oexle K, Voit T, Ancker U, Hellner KA, Speer A, Hubner C. A cysteine 3340 substitution in the dystroglycan-binding domain of dystrophin associated with Duchenne muscular dystrophy, mental retardation and absence of the ERG b-wave. Hum Mol Genet. 1996 Jul;5(7):973-5. PMID:8817332
- ↑ Goldberg LR, Hausmanowa-Petrusewicz I, Fidzianska A, Duggan DJ, Steinberg LS, Hoffman EP. A dystrophin missense mutation showing persistence of dystrophin and dystrophin-associated proteins yet a severe phenotype. Ann Neurol. 1998 Dec;44(6):971-6. PMID:9851445 doi:10.1002/ana.410440619
- ↑ Eraslan S, Kayserili H, Apak MY, Kirdar B. Identification of point mutations in Turkish DMD/BMD families using multiplex-single stranded conformation analysis (SSCA). Eur J Hum Genet. 1999 Oct-Nov;7(7):765-70. PMID:10573008 doi:10.1038/sj.ejhg.5200370
- ↑ Ortiz-Lopez R, Li H, Su J, Goytia V, Towbin JA. Evidence for a dystrophin missense mutation as a cause of X-linked dilated cardiomyopathy. Circulation. 1997 May 20;95(10):2434-40. PMID:9170407
- ↑ Feng J, Yan JY, Buzin CH, Sommer SS, Towbin JA. Comprehensive mutation scanning of the dystrophin gene in patients with nonsyndromic X-linked dilated cardiomyopathy. J Am Coll Cardiol. 2002 Sep 18;40(6):1120-4. PMID:12354438
- ↑ Feng J, Yan J, Buzin CH, Towbin JA, Sommer SS. Mutations in the dystrophin gene are associated with sporadic dilated cardiomyopathy. Mol Genet Metab. 2002 Sep-Oct;77(1-2):119-26. PMID:12359139
- ↑ 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
- ↑ Haenggi T, Fritschy JM. Role of dystrophin and utrophin for assembly and function of the dystrophin glycoprotein complex in non-muscle tissue. Cell Mol Life Sci. 2006 Jul;63(14):1614-31. PMID:16710609 doi:10.1007/s00018-005-5461-0
- ↑ Huang X, Poy F, Zhang R, Joachimiak A, Sudol M, Eck MJ. Structure of a WW domain containing fragment of dystrophin in complex with beta-dystroglycan. Nat Struct Biol. 2000 Aug;7(8):634-8. PMID:10932245 doi:10.1038/77923
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