Dystrophin is a rod-shaped cytoplasmic protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. This complex is variously known as the costamere or the dystrophin-associated protein complex. Many muscle proteins, such as α-dystrobrevin, syncoilin, synemin, sarcoglycan, dystroglycan, and sarcospan, colocalize with dystrophin at the costamere.
As of 2007, dystrophin is the longest gene known, covering 2.4 megabases (0.08% of the human genome) at locus Xp21. The primary transcript measures about 2,400 kilobases and takes 16 hours to transcribe; the mature mRNA measures 14.0 kilobases[1]. The 79 exons[2] code for a protein of over 3500 amino acid residues.[3]
Pathology
Dystrophin deficiency has been definitively established as one of the root causes of the general class of myopathies collectively referred to as muscular dystrophy. The large cytosolic protein was first identified in 1987 by Louis M. Kunkel [4], after the 1986 discovery of the mutated gene that causes Duchenne muscular dystrophy (DMD) [5].
Normal skeletal muscle tissue contains only small amounts of dystrophin (about 0.002% of total muscle protein), but its absence (or abnormal expression) leads to the development of a severe and currently incurable constellation of symptoms most readily characterized by several aberrant intracellular signaling pathways that ultimately yield pronounced myofiber necrosis as well as progressive muscle weakness and fatigability. Most DMD patients become wheelchair-dependent early in life, and the gradual development of cardiac hypertrophy—a result of severe myocardial fibrosis—typically results in premature death in the first two or three decades of life. A separate mutation in the dystrophin gene also leads to the production of defective dystrophin protein, but the nature of the mutation is such that affected patients display a much milder dystrophic phenotype and develop the disease known as Becker's muscular dystrophy (BMD).
Though its role in airway smooth muscle is not well established recent research indicates that dystrophin along with other subunits of dystrophin glycoprotein complex is associated with phenotype maturation.[6]
Interactions
Dystrophin has been shown to interact with SNTB1,[7] Syntrophin, alpha 1[8][9][10] and DTNA.[11]
References
- ^ NCBI Sequence Viewer v2.0
- ^ Strachan T and Read AP, 1999. Human molecular genetics, BIOS Scientific, New York, USA
- ^ NCBI Sequence Viewer v2.0
- ^ Hoffman E, Brown R, Kunkel L (1987). "Dystrophin: the protein product of the Duchenne muscular dystrophy locus". Cell 51 (6): 919–28. doi:10.1016/0092-8674(87)90579-4. PMID 3319190.
- ^ Monaco A, Neve R, Colletti-Feener C et al. (1986). "Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene". Nature 323 (6089): 646–50. doi:10.1038/323646a0. PMID 3773991.
- ^ Sharma P, Tran T, Stelmack GL, et al. (2008). "Expression of the dystrophin-glycoprotein complex is a marker for human airway smooth muscle phenotype maturation". Am. J. Physiol. Lung Cell Mol. Physiol. 294 (1): L57–68. doi:10.1152/ajplung.00378.2007. PMID 17993586.
- ^ Ahn, A H; Kunkel L M (Feb. 1995). "Syntrophin binds to an alternatively spliced exon of dystrophin". J. Cell Biol. (UNITED STATES) 128 (3): 363-71. ISSN 0021-9525. PMID 7844150.
- ^ Ahn, A H; Freener C A, Gussoni E, Yoshida M, Ozawa E, Kunkel L M (Feb. 1996). "The three human syntrophin genes are expressed in diverse tissues, have distinct chromosomal locations, and each bind to dystrophin and its relatives". J. Biol. Chem. (UNITED STATES) 271 (5): 2724-30. ISSN 0021-9258. PMID 8576247.
- ^ Yang, B; Jung D, Rafael J A, Chamberlain J S, Campbell K P (Mar. 1995). "Identification of alpha-syntrophin binding to syntrophin triplet, dystrophin, and utrophin". J. Biol. Chem. (UNITED STATES) 270 (10): 4975-8. ISSN 0021-9258. PMID 7890602.
- ^ Gee, S H; Madhavan R, Levinson S R, Caldwell J H, Sealock R, Froehner S C (Jan. 1998). "Interaction of muscle and brain sodium channels with multiple members of the syntrophin family of dystrophin-associated proteins". J. Neurosci. (UNITED STATES) 18 (1): 128-37. ISSN 0270-6474. PMID 9412493.
- ^ Sadoulet-Puccio, H M; Rajala M, Kunkel L M (Nov. 1997). "Dystrobrevin and dystrophin: an interaction through coiled-coil motifs". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 94 (23): 12413-8. ISSN 0027-8424. PMID 9356463.
Further reading
- Roberts RG, Gardner RJ, Bobrow M (1994). "Searching for the 1 in 2,400,000: a review of dystrophin gene point mutations". Hum. Mutat. 4 (1): 1–11. doi:10.1002/humu.1380040102. PMID 7951253.
- Tinsley JM, Blake DJ, Zuellig RA, Davies KE (1994). "Increasing complexity of the dystrophin-associated protein complex". Proc. Natl. Acad. Sci. U.S.A. 91 (18): 8307–13. doi:10.1073/pnas.91.18.8307. PMID 8078878.
- Blake DJ, Weir A, Newey SE, Davies KE (2002). "Function and genetics of dystrophin and dystrophin-related proteins in muscle". Physiol. Rev. 82 (2): 291–329. doi:10.1152/physrev.00028.2001 (inactive 2008-06-22). PMID 11917091.
- Röper K, Gregory SL, Brown NH (2003). "The 'spectraplakins': cytoskeletal giants with characteristics of both spectrin and plakin families". J. Cell. Sci. 115 (Pt 22): 4215–25. doi:10.1242/jcs.00157. PMID 12376554.
- Muntoni F, Torelli S, Ferlini A (2003). "Dystrophin and mutations: one gene, several proteins, multiple phenotypes". Lancet neurology 2 (12): 731–40. doi:10.1016/S1474-4422(03)00585-4. PMID 14636778.
- Haenggi T, Fritschy JM (2006). "Role of dystrophin and utrophin for assembly and function of the dystrophin glycoprotein complex in non-muscle tissue". Cell. Mol. Life Sci. 63 (14): 1614–31. doi:10.1007/s00018-005-5461-0. PMID 16710609.
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PDB Gallery |
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1dxx: N-TERMINAL ACTIN-BINDING DOMAIN OF HUMAN DYSTROPHIN
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1eg3: STRUCTURE OF A DYSTROPHIN WW DOMAIN FRAGMENT IN COMPLEX WITH A BETA-DYSTROGLYCAN PEPTIDE
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1eg4: STRUCTURE OF A DYSTROPHIN WW DOMAIN FRAGMENT IN COMPLEX WITH A BETA-DYSTROGLYCAN PEPTIDE
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External links
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Proteins of the cytoskeleton |
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Actins ( A1, A2, B, G1, G2)
Myosins (1A, 1B, 1C, MYH1, MYH2, MYH3, MYH4, MYH6, MYH7, MYH7B, MYH8, MYH9, MYH10, MYH11, MYH13, MYH14, MYH15, MYH16)
Tropomodulin (1, 2, 3, 4) · Troponin (T 1 2 3, C 1 2, I 1 2 3) · Tropomyosin (1, 2, 3, 4)
other related: Actinin ( 1, 2, 3, 4) · Arp2/3 complex · actin depolymerizing factors ( Cofilin ( 1, 2) · Destrin) · Gelsolin · Profilin ( 1, 2)
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Other
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type 1 and 2 ( Cytokeratin, type I, type II) · type 3 ( Desmin, GFAP, Peripherin, Vimentin) · type 4 ( Internexin, Nestin, Neurofilament, Synemin, Syncoilin) · type 5 ( Lamin A, B)
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Other
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