Dystrobrevin

Last updated
dystrobrevin, alpha
Identifiers
Symbol DTNA
NCBI gene 1837
HGNC 3057
OMIM 601239
RefSeq NM_032981
UniProt Q9Y4J8
Other data
Locus Chr. 18 q12
Search for
Structures Swiss-model
Domains InterPro
dystrobrevin, beta
Identifiers
SymbolDTNB
NCBI gene 1838
HGNC 3058
OMIM 602415
RefSeq NM_033147
UniProt O60941
Other data
Locus Chr. 2 p24
Search for
Structures Swiss-model
Domains InterPro

Dystrobrevin is a protein that binds to dystrophin in the costamere of skeletal muscle cells. In humans, there are at least two isoforms of dystrobrevin, dystrobrevin alpha and dystrobrevin beta.

Contents

Dystrobrevins are members of dystrophin-related protein family which are thought to play an important role in intracellular signal transduction and provide a membrane scaffold in muscle. Defects in dystrobrevins and their associated proteins cause a range of neuromuscular diseases such as muscular dystrophies. Dystrobrevin was first identified by isolating from the electric organ of the electric ray Torpedo californica. [1] It is a phosphoprotein, which weights 87 kDa, associated with the postsynaptic membrane at the cytoplasmic face. [2] [3] Dystrobrevin proteins have been said to participates in the formation and stability of synapses because it copurifies with acetylcholine receptors from Torpedo electric organ membranes. [4]

In 1997, an experiment was done using the yeast two-hybrid model to identify protein-protein interaction between dystrobrevin and dystrophin-associated protein complex (DPC). The evidence suggested that dystrobrevin works as a motor protein receptor that might play an important role in the transport of components of the dystrophin-associated protein complex to specific intracellular sites. [5] The DPC is expressed in both muscle and non-muscle tissues. It works as a mechanical component of cells and a dynamic multifunctional structure that can serve as a scaffold for signaling molecules. [6] The dystrophin-associated proteins can be divided into three groups depending on their cellular localization: extracellular, transmembrane, and cytoplasmic. Dystrobrevin protein is a part of the cytoplasmic complex and an intracellular protein that binds directly to dystrophin.

In invertebrates, dystrobrevin is present as a single protein, while in vertebrates, there are two isoforms, a-dystrobrevin (DTNA) and β-dystrobrevin (DTNB). [7] Each dystrobrevin isoform has a unique structure with carboxyl termini and sequence homology with the cysteine-rich carboxyl-terminal region of dystrophin. This region of similarity can be divided into several functional domains such as two coiled-coil regions, two EF hands or a ZZ-type zinc finger. [6]

Evolutionary History

A phylogenic tree for the dystrophin protein family has been proposed based on the analysis of known dystrobrevin and dystrophin sequences that were extracted from human and fruit fly proteins. [8] The phylogeny postulated a non-metazoan ancestor that had a single dystrophin/dystrobrevin protein, which probably functioned as a homodimer. At some point before the last common ancestor of metazoans, a duplication lead to a separation of dystrophin and dystrobrevin genes, their protein products forming a heterodimer of more specialized components. In vertebrates, two other duplications occurred. The first gave rise to DRP2, a common ancestor of dystrophin and utrophin, and to α- and β-dystrobrevin. [9] The second resulted in the separate dystrophin and utrophin genes. In addition, sequence alignments of dystrophin family protein strongly support the concept that two distinct subfamilies exist, one consisted of dystrophin, utrophin, and DRP2 and the other consisted of α- and β-dystrobrevin.

Classification

Dystrobrevins are the product of two distinct genes coding for two highly homologous proteins, α- and β-dystrobrevin. Several different transcripts are derived from each gene by alternative splicing or initiation sites, generating a large family of dystrobrevin isoforms.

Alpha Dystrobrevin

The α-dystrobrevin structure is homologous to the cysteine-rich carboxy-terminal domain of dystrophin. [10] This protein is expressed predominantly in skeletal muscle, heart, lung, and central nervous system. It is thought to be involved in synaptic transmission at the neuromuscular junction and in intracellular signaling.

Beta Dystrobrevins

The β-dystrobrevin, is only found in non-muscle tissues, predominantly expressed in kidney and brain, and forms complexes with dystrophin-associated proteins and syntrophin in liver and brain. [7] In the brain, β-dystrobrevin associates with dystrophin isoforms in the cortex, hippocampus, and Purkinje neurons.

Gene and transcripts

The human α-dystrobrevin gene is localized to chromosome 18 and consists of 23 coding exons. [11] α-Dystrobrevin is known to be subject to extensive splicing regulation. The alternative usage of three exons 21, 17B, and 11B generates RNA molecules with different lengths encoding three major α-dystrobrevin products in human skeletal muscle: α-dystrobrevin 1, α-dystrobrevin 2, and α-dystrobrevin 3. [11] Due to alternative splicing within the coding regions, supplemental diversity is observed referred to as variable regions 1, 2, and 3 [12] Firstly, variable region 1 (vr1) consists of a short exon containing three amino acids. In mice, the transcripts including this exon are primarily restricted to the brain [12] [13] but are present in the brain, heart, and skeletal muscle in humans. [11] Secondly, variable region 2 (vr2) consists of exons 17A and 17B which encodes the unique C-terminal tail of α-dystrobrevin 2. Lastly, variable region 3 (vr3) consists of exons 11A, 11B, and 12, and exon 11B encodes the unique C-terminal tail of α-dystrobrevin 3. In mouse skeletal muscle, the splicing of vr2 and vr3 has been reported to be developmentally controlled. [12] [14]

The human β-dystrobrevin gene was localized to the short arm of chromosome 2. Pair-wise comparison between α- and β-dystrobrevin sequences revealed that the two dystrobrevins have 76% identity.

Structure of protein

α- and β-Dystrobrevin proteins structure consisted of four major domains, a ZZ -type zinc finger domain, two EF-hand regions, an α-helical coiled-coil domain containing a dystrophin binding site, and a tyrosine kinase substrate domain. [4] α-Dystrobrevin 1, α-Dystrobrevin 2, and α-dystrobrevin 3 binds to the dystrophin-glycoprotein complex via the amino-terminus region. [15] α-Dystrobrevin 1 and α-Dystrobrevin 2 bind dystrophin through a highly conserved coiled-coil domain. [4] [10]

β-dystrobrevin is detected as a 61-kDa protein in the brain, kidney, liver, and lung. β-dystrobrevin can be distinguished from α-dystrobrevin 2 because it has lower relative mobility. Slight differences in the size of the β-dystrobrevin were observed in the brain compared with the kidney, liver, and lung.

Localization

α-Dystrobrevin 1 is localized in the sarcolemma and is abundant at the neuromuscular junction, and concentrated in the crest of the junctional folds. [1] α-Dystrobrevin 2 is localized around the entire circumference of the sarcolemmal plasma membrane including the neuromuscular junction. α-Dystrobrevin 2 primarily co-localizes with dystrophin at the neuromuscular junction, while α-Dystrobrevin 1 co-localizes with both dystrophin and utrophin. [16] α-Dystrobrevin 3 has been thought to be located on the cytoplasmic site.  

The location and expression pattern of β-dystrobrevin was observed by using Northern blots of mouse RNAs. A single 2.5-kb transcript was detected predominantly in the brain and kidney and to a lesser extent in liver and lung. No β-dystrobrevin transcripts were detected in skeletal and cardiac muscle even after long exposures. [17] This evidence suggested that the β-dystrobrevin transcript was weakly expressed or absent in muscle.

Function

The fundamental role of the dystrobrevin protein family remains unclear. Much of what we do know has been observation from biochemical studies of associated proteins and the phenotypic consequences of their loss.

α-Dystrobrevin proteins are suggested to involve in the structural integrity of muscle cells by interacting with cytoskeletal binding proteins and signal transduction by interacting with syntrophin. Firstly, α-Dystrobrevin is a component of the dystrophin-glycoprotein complex, which is extremely useful for maintenance of the skeletal cell integrity. α-dystrobrevin associated with dystrophin at its coil-coil region and with a sarcoglycan-protein complex at the amino-terminal. [18] It has been proposed to function as a structural scaffold linking the dystrophin-glycoprotein complex to the intracellular cytoskeleton. Based on the yeast two-hybrid system and co-immunoprecipitation analysis, three other proteins were identified as additional to α-dystrobrevin-binding proteins: β-synemin, syncoilin, and dysbindin. [10] [18] Syncoilin and β-synemin are both intermediate filament proteins. The intermediate filaments are responsible for forming the structure of the cell cytoskeleton and providing mechanical stability to the cells. Syncoilin co-localizes with α-dystrobrevin at both the neuromuscular junction and sarcolemma while β-Synemin co-localizes with α-dystrobrevin only at the neuromuscular junction. The interaction of α-dystrobrevin and β-synemin provides an additional connection between the intermediate filament system and the dytsrophin-glycoprotein complex. Dysbindin is located at the sarcolemma, and its expression in skeletal muscle is relatively low. Secondly, α-Dystrobrevins participate in intracellular signaling since they bind directly with syntrophin, which is a modular adaptor protein thought to be involved in signal transduction. In skeletal muscle, syntrophins have four main isoforms: α-, β1-, β2-, and γ2-syntrophin. [19] [20]

β-dystrobrevin has been thought to play a structural role in the composition of the dystrophin-associated protein complex in the brain which differs from that in muscle. β-dystrobrevin coimmunoprecipitates with the dystrophin isoforms Dp71 and Dp140 in the brain. Dp140 is concentrated in the brain microvasculature [17] while the Dp71 transcript is found throughout the brain but is particularly abundant in the dentate gyrus of the temporal lobe, and the olfactory bulb.

Dystrobrevins and muscle diseases

The consequences of null mutation are known for humans and rodents in the case of dystrophin, utrophin, and α-dystrobrevin, and for nematode in the case of dystrophin and dystrobrevin. In human, the Duchenne muscular dystrophy is a well-known muscle disease which highlights the importance of dystrophin/ dystrobrevin protein to function of muscle tissue. Duchenne muscular dystrophy (DMD) is a fatal progressive disease of both cardiac and skeletal muscle resulting from the mutations in the DMD gene and loss of the protein dystrophin. [21] The lack of dystrophin that causes Duchenne muscular dystrophy results in secondary loss of other dystrophin-complex components from the membrane. The loss of protein dystrophin ultimately leads to a lethal syndrome of skeletal and cardiac myopathy, stationary night blindness, mental retardation, a cardiac-conduction defect, and a subtle smooth-muscle defect. [22] Some of these traits are also found in a subset of the limb-girdle muscular dystrophies that result from sarcoglycan defects. α-Dystrobrevin proteins were found absent in a heart that is highly susceptible to injury during cardiac stress. [22] The dystrobrevin loss resulted from a weakening of dystrophin's interaction with the membrane-bound dystrophin-glycoprotein complex, and lead to a significant loss of membrane integrity.

Related Research Articles

<span class="mw-page-title-main">Dystrophin</span> Rod-shaped cytoplasmic protein

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 (DAPC). Many muscle proteins, such as α-dystrobrevin, syncoilin, synemin, sarcoglycan, dystroglycan, and sarcospan, colocalize with dystrophin at the costamere. It has a molecular weight of 427 kDa

<span class="mw-page-title-main">Tropomyosin</span> Protein

Tropomyosin is a two-stranded alpha-helical, coiled coil protein found in many animal and fungal cells. In animals, it is an important component of the muscular system which works in conjunction with troponin to regulate muscle contraction. It is present in smooth and striated muscle tissues, which can be found in various organs and body systems, including the heart, blood vessels, respiratory system, and digestive system. In fungi, tropomyosin is found in cell walls and helps maintain the structural integrity of cells.

Derek Blake was, until 2007, the Isobel Laing Post-Doctoral Fellow in Biomedical Sciences, and the Wellcome Trust Senior Fellow in Basic Biomedical Science, Oriel College, Oxford.

The sarcoglycans are a family of transmembrane proteins involved in the protein complex responsible for connecting the muscle fibre cytoskeleton to the extracellular matrix, preventing damage to the muscle fibre sarcolemma through shearing forces.

<span class="mw-page-title-main">Dystroglycan</span> Protein

Dystroglycan is a protein that in humans is encoded by the DAG1 gene.

<span class="mw-page-title-main">Utrophin</span> Mammalian protein found in Homo sapiens

Utrophin is a protein that in humans is encoded by the UTRN gene. The name is a short form for ubiquitous dystrophin.

<span class="mw-page-title-main">Synemin</span> Protein found in humans

Synemin, also known as desmuslin, is a protein that in humans is encoded by the SYNM gene. Synemin is an intermediate filament (IF) family member. IF proteins are cytoskeletal proteins that confer resistance to mechanical stress and are encoded by a dispersed multigene family. This protein has been found to form a linkage between desmin, which is a subunit of the IF network, and the extracellular matrix, and provides an important structural support in muscle.

<span class="mw-page-title-main">Sarcospan</span>

Originally identified as Kirsten ras associated gene (KRAG), sarcospan (SSPN) is a 25-kDa transmembrane protein located in the dystrophin-associated protein complex of skeletal muscle cells, where it is most abundant. It contains four transmembrane spanning helices with both N- and C-terminal domains located intracellularly. Loss of SSPN expression occurs in patients with Duchenne muscular dystrophy. Dystrophin is required for proper localization of SSPN. SSPN is also an essential regulator of Akt signaling pathways. Without SSPN, Akt signaling pathways will be hindered and muscle regeneration will not occur.

The syntrophins are a family of five 60-kiloDalton proteins that are associated with dystrophin, the protein associated with Duchenne muscular dystrophy and Becker muscular dystrophy. The name comes from the Greek word syntrophos, meaning "companion." The five syntrophins are encoded by separate genes and are termed α, β1, β2, γ1, and γ2. Syntrophin was first identified as a dystrophin-associated protein present in the Torpedo electric organ. Subsequently, α-syntrophin was shown to be the predominant isoform in skeletal muscle where it is localized on the sarcolemma and enriched at the neuromuscular junction. The β-syntrophins and γ2-syntrophin are also present in skeletal muscle but also are in most other tissues. The expression of γ1-syntrophin is mostly confined to brain. The syntrophins are adaptor proteins that use their multiple protein interaction domains to localize a variety of signaling proteins to specific intracellular locations. α-Syntrophin binds to nNOS in the dystrophin-associated glycoprotein complex in skeletal muscle cells. There it produces NO upon muscle contraction leading to dilation of the arteries in the local area.

<span class="mw-page-title-main">Syntrophin, alpha 1</span> Protein-coding gene in the species Homo sapiens

Alpha-1-syntrophin is a protein that in humans is encoded by the SNTA1 gene. Alpha-1 syntrophin is a signal transducing adaptor protein and serves as a scaffold for various signaling molecules. Alpha-1 syntrophin contains a PDZ domain, two Pleckstrin homology domain and a 'syntrophin unique' domain.

<span class="mw-page-title-main">TPM2</span> Protein-coding gene in the species Homo sapiens

β-Tropomyosin, also known as tropomyosin beta chain is a protein that in humans is encoded by the TPM2 gene. β-tropomyosin is striated muscle-specific coiled coil dimer that functions to stabilize actin filaments and regulate muscle contraction.

<span class="mw-page-title-main">SGCB</span> Protein-coding gene in the species Homo sapiens

Beta-sarcoglycan is a protein that in humans is encoded by the SGCB gene.

<span class="mw-page-title-main">Delta-sarcoglycan</span> Mammalian protein found in Homo sapiens

Delta-sarcoglycan is a protein that in humans is encoded by the SGCD gene.

<span class="mw-page-title-main">SNTB2</span> Protein-coding gene in the species Homo sapiens

Beta-2-syntrophin is a protein that in humans is encoded by the SNTB2 gene.

<span class="mw-page-title-main">SGCA</span> Protein-coding gene in the species Homo sapiens

Alpha-sarcoglycan is a protein that in humans is encoded by the SGCA gene.

<span class="mw-page-title-main">SGCG</span> Protein-coding gene in the species Homo sapiens

Gamma-sarcoglycan is a protein that in humans is encoded by the SGCG gene. The α to δ-sarcoglycans are expressed predominantly (β) or exclusively in striated muscle. A mutation in any of the sarcoglycan genes may lead to a secondary deficiency of the other sarcoglycan proteins, presumably due to destabilisation of the sarcoglycan complex. The disease-causing mutations in the α to δ genes cause disruptions within the dystrophin-associated protein (DAP) complex in the muscle cell membrane. The transmembrane components of the DAP complex link the cytoskeleton to the extracellular matrix in adult muscle fibres, and are essential for the preservation of the integrity of the muscle cell membrane.

<span class="mw-page-title-main">SNTB1</span> Protein-coding gene in the species Homo sapiens

Beta-1-syntrophin is a protein that in humans is encoded by the SNTB1 gene.

<span class="mw-page-title-main">Dystrobrevin alpha</span> Protein found in humans

Dystrobrevin alpha is a protein that in humans is encoded by the DTNA gene.

<span class="mw-page-title-main">Dystrobrevin beta</span> Protein-coding gene in the species Homo sapiens

Dystrobrevin beta is a protein which in humans is encoded by the DTNB gene.

References

  1. 1 2 Yeadon JE, Lin H, Dyer SM, Burden SJ (November 1991). "Dystrophin is a component of the subsynaptic membrane". The Journal of Cell Biology. 115 (4): 1069–76. doi:10.1083/jcb.115.4.1069. PMC   2289946 . PMID   1720119.
  2. ↑ Carr C, Fischbach GD, Cohen JB (October 1989). "A novel 87,000-Mr protein associated with acetylcholine receptors in Torpedo electric organ and vertebrate skeletal muscle". The Journal of Cell Biology. 109 (4 Pt 1): 1753–64. doi:10.1083/jcb.109.4.1753. PMC   2115790 . PMID   2793938.
  3. ↑ Butler MH, Douville K, Murnane AA, Kramarcy NR, Cohen JB, Sealock R, Froehner SC (March 1992). "Association of the Mr 58,000 postsynaptic protein of electric tissue with Torpedo dystrophin and the Mr 87,000 postsynaptic protein". The Journal of Biological Chemistry. 267 (9): 6213–8. doi: 10.1016/S0021-9258(18)42683-X . PMID   1556129.
  4. 1 2 3 Sadoulet-Puccio HM, Rajala M, Kunkel LM (November 1997). "Dystrobrevin and dystrophin: an interaction through coiled-coil motifs". Proceedings of the National Academy of Sciences of the United States of America. 94 (23): 12413–8. Bibcode:1997PNAS...9412413S. doi: 10.1073/pnas.94.23.12413 . PMC   24974 . PMID   9356463.
  5. ↑ Roberts RG (2001). "Dystrophins and dystrobrevins". Genome Biology. 2 (4): REVIEWS3006. doi: 10.1186/gb-2001-2-4-reviews3006 . PMC   138928 . PMID   11305946.
  6. 1 2 Constantin B (February 2014). "Dystrophin complex functions as a scaffold for signalling proteins". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1838 (2): 635–42. doi: 10.1016/j.bbamem.2013.08.023 . PMID   24021238.
  7. 1 2 Blake DJ, Nawrotzki R, Loh NY, Górecki DC, Davies KE (January 1998). "beta-dystrobrevin, a member of the dystrophin-related protein family". Proceedings of the National Academy of Sciences of the United States of America. 95 (1): 241–6. Bibcode:1998PNAS...95..241B. doi: 10.1073/pnas.95.1.241 . PMC   18188 . PMID   9419360.
  8. ↑ Roberts RG, Bobrow M (April 1998). "Dystrophins in vertebrates and invertebrates". Human Molecular Genetics. 7 (4): 589–95. doi: 10.1093/hmg/7.4.589 . PMID   9499411.
  9. ↑ Holland PW, Garcia-Fernàndez J, Williams NA, Sidow A (1994). "Gene duplications and the origins of vertebrate development". Development. 1994: 125–33. doi:10.1242/dev.1994.Supplement.125. PMID   7579513.
  10. 1 2 3 Blake DJ, Tinsley JM, Davies KE, Knight AE, Winder SJ, Kendrick-Jones J (April 1995). "Coiled-coil regions in the carboxy-terminal domains of dystrophin and related proteins: potentials for protein-protein interactions". Trends in Biochemical Sciences. 20 (4): 133–5. doi:10.1016/s0968-0004(00)88986-0. PMID   7770909.
  11. 1 2 3 Sadoulet-Puccio HM, Feener CA, Schaid DJ, Thibodeau SN, Michels VV, Kunkel LM (May 1997). "The genomic organization of human dystrobrevin". Neurogenetics. 1 (1): 37–42. doi:10.1007/s100480050006. PMID   10735273. S2CID   22588879.
  12. 1 2 3 Blake DJ, Nawrotzki R, Peters MF, Froehner SC, Davies KE (March 1996). "Isoform diversity of dystrobrevin, the murine 87-kDa postsynaptic protein". The Journal of Biological Chemistry. 271 (13): 7802–10. doi: 10.1074/jbc.271.13.7802 . PMID   8631824.
  13. ↑ Nawrotzki R, Loh NY, Ruegg MA, Davies KE, Blake DJ (September 1998). "Characterisation of alpha-dystrobrevin in muscle". Journal of Cell Science. 111 ( Pt 17) (17): 2595–605. doi:10.1242/jcs.111.17.2595. PMID   9701558.
  14. ↑ Enigk RE, Maimone MM (October 1999). "Differential expression and developmental regulation of a novel alpha-dystrobrevin isoform in muscle". Gene. 238 (2): 479–88. doi:10.1016/S0378-1119(99)00358-3. PMID   10570976.
  15. ↑ Yoshida M, Hama H, Ishikawa-Sakurai M, Imamura M, Mizuno Y, Araishi K, et al. (April 2000). "Biochemical evidence for association of dystrobrevin with the sarcoglycan-sarcospan complex as a basis for understanding sarcoglycanopathy". Human Molecular Genetics. 9 (7): 1033–40. doi: 10.1093/hmg/9.7.1033 . PMID   10767327.
  16. ↑ Peters MF, Sadoulet-Puccio HM, Grady MR, Kramarcy NR, Kunkel LM, Sanes JR, et al. (September 1998). "Differential membrane localization and intermolecular associations of alpha-dystrobrevin isoforms in skeletal muscle". The Journal of Cell Biology. 142 (5): 1269–78. doi:10.1083/jcb.142.5.1269. PMC   2149339 . PMID   9732287.
  17. 1 2 Blake DJ, Nawrotzki R, Loh NY, Górecki DC, Davies KE (January 1998). "beta-dystrobrevin, a member of the dystrophin-related protein family". Proceedings of the National Academy of Sciences of the United States of America. 95 (1): 241–6. Bibcode:1998PNAS...95..241B. doi: 10.1073/pnas.95.1.241 . PMC   18188 . PMID   9419360.
  18. 1 2 Böhm SV, Roberts RG (2009). "Expression of members of the dystrophin, dystrobrevin, and dystrotelin superfamily". Critical Reviews in Eukaryotic Gene Expression. 19 (2): 89–108. doi:10.1615/critreveukargeneexpr.v19.i2.10. PMID   19392646.
  19. ↑ Ahn AH, Freener CA, Gussoni E, Yoshida M, Ozawa E, Kunkel LM (February 1996). "The three human syntrophin genes are expressed in diverse tissues, have distinct chromosomal locations, and each bind to dystrophin and its relatives". The Journal of Biological Chemistry. 271 (5): 2724–30. doi: 10.1074/jbc.271.5.2724 . PMID   8576247.
  20. ↑ Ahn AH, Kunkel LM (February 1995). "Syntrophin binds to an alternatively spliced exon of dystrophin". The Journal of Cell Biology. 128 (3): 363–71. doi:10.1083/jcb.128.3.363. PMC   2120343 . PMID   7844150.
  21. ↑ "About Duchenne Muscular Dystrophy". Genome.gov. Retrieved 2020-04-30.
  22. 1 2 Strakova J, Dean JD, Sharpe KM, Meyers TA, Odom GL, Townsend D (November 2014). "Dystrobrevin increases dystrophin's binding to the dystrophin-glycoprotein complex and provides protection during cardiac stress". Journal of Molecular and Cellular Cardiology. 76: 106–15. doi:10.1016/j.yjmcc.2014.08.013. PMC   4271192 . PMID   25158611.
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