Dystroglycan
| Dystroglycan | ||
|---|---|---|
| other names |
Distrophin associated glycoprotein 1 |
|
| Properties of human protein | ||
| Identifier | ||
| Gene name | DAG 1 | |
| External IDs | ||
| Orthologue | ||
| human | House mouse | |
| Entrez | 1605 | 13138 |
| Ensemble | ENSG00000173402 | ENSMUSG00000039952 |
| UniProt | Q14118 | Q62165 |
| Refseq (mRNA) | NM_001165928 | NM_001276481 |
| Refseq (protein) | NP_001159400 | NP_001263410 |
| Gene locus | Chr 3: 49.47 - 49.54 Mb | Chr 9: 108.2 - 108.26 Mb |
| PubMed search | 1605 |
13138
|
Dystroglycan is a glycoprotein which, as a dystroglycan complex, forms the central component of the dystrophin-glycoprotein complex . It was first cloned in the course of research into the fundamentals of muscular dystrophies.
Expression and structure
It is encoded by the DAG1 gene on two exons that are separated from one another by a large intron . By splicing arise as two subunits: α- or β-dystroglycan. The 156 kilodalton , highly glycosylated and extracellular α-dystroglycan is characterized by an N terminus , whereas the only 43 kilodalton and poorly glycosylated transmembrane protein β-dystroglycan has a C terminus . The degree of glycosylation is regulated specifically for the respective tissue and the level of development. However, both are only generated by a single, 5.8 kb mRNA , which initially codes for a 95 kilodalton precursor protein that first undergoes various conversion steps before the α- and β-dystroglycan are formed. Dystroglycan is expressed in a large number of adult and fetal tissues.
function
α- and β-dytroglycan together form the dystroglycan complex, the central element of the dystrophin-glycoprotein complex. The glycosylation of the dystroglycan is of crucial importance for the interaction with the binding partners and thus also for the shape of the entire dystrophin-glycoprotein complex: The EZM ( extracellular matrix ) molecules Agrin , Perlecan and various other laminins become dependent on calcium via Laminin-G similar (LG) domains attached to the sugar side chains of α-dytroglycan. In contrast, the following interactions / bonds are independent of such sugar residues: the binding of biglycan to α-dytroglycan, the interaction of α-dystroglycan via a 35 amino acid domain in its C -terminus with the extracellular N -terminus of β-dystroglycan and more important the binding of dystrophin to the proline- rich, N -terminal end of β-dystroglycan via a WW domain that is additionally reinforced by dystrophin. This interaction with dystrophin can be regulated by tyrosine phosphorylation in the intracellular C-terminal part of β-dystroglyca. The connection of the dystrophin-glycoprotein complex with the cytoskeleton occurs via the binding of F-actin to the N -terminal area of dystrophin. Taken together, these protein bonds mean a connection between the extracellular matrix and the cytoskeleton and thus a significant strengthening of the muscle fiber, which enables it to compensate for the forces that act on the cell membrane during muscle contraction.
Clinical reference
If dystroglycan is abnormally glycosylated, it results in various muscular dystrophies, which can range from mild to severe with abnormalities of the eyes and brain. So far, mutations in six different genes have been blamed for such abnormal glycosylation: POMT1 , POMT2 , POMGNT1 , FKTN , FKRP and LARGE . These abnormalities are also known as dystroglycanophathy (English "distroglycanophathy"). Specifically, mutations at FKTN gene can contribute to the so-called muscular dystrophy, Fukuyama (engl. "Fukuyama congenital muscular dystrophy") result because characterized α-dystroglycan is glycosylated defective, or muscle-eye-brain disease , or Walker-Warburg syndrome to lead.
Individual evidence
- ↑ a b c Jörn E. Schröder: The function of dystroglycan in the development of the central nervous system . Mainz, 2003, p. 1 (Dissertation to obtain the degree "Doctor of Natural Sciences")
- ↑ O. Ibraghimov-Beskrovnaya, A. Milatovich, T. Ozcelik, B. Yang, K. Koepnick, U. Francke and KP Campbell: Human dystroglycan: skeletal muscle cDNA, genomic structure, origin of tissue specific isoforms and chromosomal localization . In: Human Molecular Genetics . 2, No. 10, October 1993, pp. 1651-1657. PMID 8268918 .
- ↑ a b c d e dystroglycan. In: Online Mendelian Inheritance in Man . (English)
- ↑ O. Ibraghimov-Beskrovnaya, JM Ervasti, CJ Leveille, CA Slaughter, SW Sernett and KP Campbell: Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix . In: Nature . 355, February 192, p. 6362. doi : 10.1038 / 355696a0 . PMID 1741056 .
- ↑ C. Godfrey et al .: Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan . In: Brain . No. 130 (Pt 10), October 2007, pp. 2725-2735. doi : 10.1093 / brain / awm212 . PMID 17878207 .
- ↑ K. Matsumura, I. Nonaka and KP Campbell: Abnormal expression of dystrophin-associated proteins in Fukuyama-type congenital muscular dystrophy . In: The Lancent . 341, No. 8844, February 1993, pp. 521-522. doi : 10.1016 / 0140-6736 (93) 90279-P . PMID 8094772 .
- ↑ Dystroglycan. In: Online Mendelian Inheritance in Man . (English).