Dystrobrevins

Dystrobrevins are a small family of dystrophin-related proteins encoded by two genes, one of which—Q-dystrobrevin—encodes at least three proteins all expressed in cardiac and skeletal muscle. o-Dystrobrevin is a key component of the DPC, and its loss results in neuromuscular junction defects and muscular dystrophy. It is a cytoplasmic protein indirectly linked with the transmembrane sarcoglycan components via dystrophin and other components of the DPC (Fig. 4) (Blake and Martin-Rendon, 2002). Recently, two novel type IV IF proteins—syncoilin (Newey et al.,... 

Syncoilin is highly expressed in skeletal and cardiac muscle and is localized to the neuromuscular junction, sarcolemma, and Z-lines. Likewise, desmuslin is expressed in heart and skeletal muscle and localized at Z-lines. It was shown that syncoilin and desmin interact directly, but do not coassemble into filaments in fact, evidence suggests that syncoilin does not participate in filament formation at all. It was proposed that syncoilin helps anchor the desmin IF network at the sarcolemma and the neuromuscular junction (Poon et al, 2002). More recent work has analyzed patients with a desmin-related cardiomyopathy in which patients with desmin accumulation also exhibit an upregulation of syncoilin and accumulation of other elements of the DPC. These defects were correlated with a disappearance of both o-dystrobrevin-l and neuronal nitric oxide... 

Mizuno, Y., Thompson, T. G., Guyon, J. R., Lidov, H. G., Brosius, M., Imamura, M., Ozawa, E., Watkins, S. C., and Kunkel, L. M. (2001). Desmuslin, an intermediate filament protein that interacts with alpha-dystrobrevin and desmin. Proc. Natl. Acad. Sci. USA 98, 6156-6161. 

Newey, S. E., Howman, E. V., Ponting, C. P., Benson, M. A., Nawrotzki, R., Loh, N. Y., Davies, K E., and Blake, D. J. (2001). Syncoilin, a novel member of the intermediate filament superfamily that interacts with alpha-dystrobrevin in skeletal muscle. / Biol. Chem. 276, 6645—6655. 

Within the skeletal musculature, dystrophin plays an important role in maintaining the integrity of the sarcolemmal membrane. Dystrophin is not able to perform this task alone and interacts with a number of other proteins that include dystroglycans, sarcoglycans, dystrobrevins, syntrophins, and sarcospan (Straub and Campbell, 1997). Mutation of dystrophin or, indeed,... 

Sadoulet-Puccio, H.M., Rajala, M., and Kunkel, L.M., 1997, Dystrobrevin and dystrophin an interaction through coiled-coil motifs, Proc Natl Acad Sci USA, 94, pp 12413-12418. 

As mentioned earlier, dysbindin-2 and -3 differ from dysbindin-1 in their lack of a CCD and predicted tyrosine and PKB phosphorylation sites. The lack of a CCD probably accounts for the failure of dysbindin-2B, unlike dysbindin-1, to bind P-dystrobrevin (Nazarian et al., 2006). Dysbindin-2 and -3 differ from each other in several respects. First, dysbindin-2 has a higher degree of sequence identity to dysbindin-1 of the same species. In humans, for example, the sequence identity to dysbindin-1 is 60% for dysbindin-2 isoforms, but only 46-51% for dysbindin-3 isoforms. Second, unlike both dysbindin-1 and -3,... 

Localization of dysbindin-1 near the sarcolemma is not dependent upon its association with a-dystrobrevin or myospryn. Benson et al. (2001) found that sarcolemmal levels of dysbindin-1 are increased in the mdx mouse, an animal model of Duchenne muscular dystrophy. Yet mdx mice also display decreased sarcolemmal levels of a-dystrobrevin (Benson et al., 2001) and myospryn (Reynolds et al., 2008). The sarcolemmal association is more likely due to other known or candidate-binding partners of dysbin-din-1, specifically pallidin, snapin, and rab 11, which are all increased along with dysbindin-1 in mdx muscle (Nazarian et al., 2006). But the increases in pallidin and dysbindin-1 are not related to muscular dystrophy since there are no apparent abnormalities in the muscles or motor behavior of pallid mice (Nazarian et al., 2006), which are deficient in pallidin and dysbindin-1 (Li et al., 2003). 

We began this review with the question that led to the discovery of dysbindin-1, namely what disrupted protein interactions of dystrobrevin may help account for the cognitive deficits in Duchenne and Becker muscular dystrophy The discovery of dysbindin-1 has not led to an answer to that question, but has led to the discovery that abnormalities in the DTNBP 1 gene or in levels of its protein product do affect cognition in normal individuals and in schizophrenia cases. Establishing the mechanisms responsible for that effect is perhaps the most important topic of future basic and translational research on dysbindin-1. 

Benson MA, Newey SE, Martin-Rendon E, Hawkes R, Blake DJ. 2001. Dysbindin, a novel coiled-coil-containing protein that interacts with the dystrobrevins in muscle and brain. J Biol Chem 276 24232-24241. 

Blake DJ, Nawrotzki R, Loh NY, Gorecki DC, Davies KE. 1998. B-dystrobrevin, a member of the dystrophin-related protein family. Proc Natl Acad Sci USA 95 241-246. 

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