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Utrophin

Page updated 9/10/02

A ubiquitously expressed analog of dystrophin which forms a link between the plasma-membrane and the underlying actin-based cytoskeleton. 

 

Actin binding
Utrophin binds actin through tandem CH-domains as do the various other actin-binding proteins in the spectrin super-family.  

 

Utrophin a cure for Muscular Dystrophin?
The mouse model for muscular dystrophy, the MDX mouse, is not very good as this mouse lacks the phenotype of muscle wasting and degeneration ().  This is largely because in mice, utrophin is also expressed in muscle and this compensates for the lack of functional dystrophin.  Mice lacking both utrophin and dystrophin exhibit the MD phenotype ().  There is good reason to suppose that utrophin could compensate for dystrophin in humans too as the muscles of the human eye (the ocular muscles) remain unaffected by MD, and express utrophin ().

 

SteveWinder Lab in Glasgow, Scotland CH-domains Dystrophin

References:-

Belkin, A. M. & Burridge, K. (1995) Association of aciculin with dystrophin and utrophin. J. Biol. Chem. 270, 6328-6337.

Blake, D. J., Schofield, J. N., Zuellig, R. A., Górecki, D. C., Phelps, S. R., Barnard, E. A., Edwards, Y. H. & Davies, K. E. (1995) G-Utrophin, the autosomal homologue of dystrophin Dp116, is expressed in sensory ganglia and brain. PNAS. 92, 3697-3701.

Burton, E. A., Tinsley, J. M., Holzfeind, P. J., Rodriques, N. R. & Davies, K. E. (1999) A second promotor provides an alternative target for therapeutic up-regulation of utrophin in Duchenne muscular dystrophy. PNAS. 96, 14025-14030.

Byers, T. J., Beggs, A. H., McNally, E. M. & Kunkel, L. M. (1995) Novel actin crosslinker superfamily member identified by a two step degenerate PCR procedure. FEBS letters. 368, 500-504.

Connolly, A. M., Keeling, R. M., Mehta, S., Pestronk, A. & Sanes, J. R. (2001) Three mouse models of muscular dystrophy: the natural history of strength and fatigue in dystrophin-dystrophin/utrophin-, and laminin a2-deficient mice. Neuromuscular Disorders. 11, 703-712.

Deconinck, A. E., Rafael, J. A., Skinner, J. A., Brown, S. C., Potter, A. C., Metzinger, L., Watt, D. J., Dickson, J. G., Tinsley, J. M. & Davies, K. E. (1997) Utrophin-dystrophin -deficient mice as a model for duchenne muscular dystrophy. Cell. 90, 717-727.

Galkin, V., Orlova, A., VanLoock, M. S., Rybakova, I. N., Ervasti, J. M. & Egelman, E. H. (2002) The utrophin actin-binding domain binds F-actin in two different modes: implications for the spectrin superfamily of proteins. J.Cell Biol. 157, 243-251.

Grady, R. M., Teng, H., Nichol, M. C., Cunningham, J. C., Wilkinson, R. S. & Sanes, J. R. (1997) Skeletal and cardiac myopothies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy. Cell. 90, 729-738.

Gramolini, A. O., Burton, E. A., Tinsley, J. M., Ferns, M. J., Cartaud, A., Cartaud, J., Davies, K. E., Lunde, J. A. & Jasmin, B. J. (1998) Muscle and neural isoforms of agrin increase utrophin expression in cultured myotubes via a transcriptional regulatory mechanism. J.Biol.Chem. 273, 736-743.

Guo, W.-X. A., Nichol, M. & Merlie, J. P. (1996) Cloning and expression of full length mouse utrophin: the differential association of utrophin and dystrophin with AChR clusters. FEBS letters. 398, 259-264.

James, M., Nuttal, A., Ilsley, J. L., Ottersbach, K., Tinsley, J. M., Sudol, M. & Winder, S. J. (2000) Adhesion-dependent tyrosine phosphorylation of b-dystroglycan regulates its interaction with urtophin., J.Cell Sci. 113, 1717-1726.

Keep, N. H., Norwood, F. L. M., Moores, C. A., Winder, S. J. & Kendrick-Jones, J. (1999) The 2.0Ć structure of the second calponin homology domain from the actin-binding region of the dystrophin homologue utrophin. J.Mol.Biol. 285, 1257-1264.

Khurana, T. S., Watkins, S. C. & Kunkel, L. M. (1992) The subcellular distribution of chromosome 6-encoded dystrophin-related protein in the brain. J.Cell Biol. 119, 357-366.

Love, D. R., Hill, D. F., Dickson, G., Spurr, N. K., Byth, B. C., Marsden, R. F., Walsh, F. S., Edwards, Y. H. & Davies, K. E. (1989) An autosomal transcript in skeletal muscle with homology to dystrophin. Nature. 339, 55-58.

Man, N. t., Thanh, L. T., Blake, D. J., Davies, K. E. & Morris, G. E. (1992) Utrophin, the autosomal homolgue of dystrophin, is widely-expressed and membrane-associated in cultured cell lines. FEBS letters. 313, 19-22.

Moores, C. A., Keep, N. H. & Kendrick-Jones, J. (2000) Structure of utrophin actin-binding domain bound to F-actin reveals binding by an induced fit mechanism. J.Mol.Biol. 297, 465-480.

Moores, C. A. & Kendrick-Jones, J. (2000) Biochemical characterisation of the actin-binding properties of utrophin. Cell Motility Cytoskeleton. 46, 116-128.

Morris, G. E., Man, N.-t., Huyen, N.-t. H., Pereboev, A., Kendrick-Jones, J. & Winder, S. J. (1999) Disruption of the utrophin-actin interaction by monoclonal antibodies and prediction of an actin-binding surface of utrophin. Biochem. J. 337, 119-123.

Porter, J. D., Rafael, J. A., Ragusa, R. J., Bruechner, J. K., Trickett, J. I. & Davies, K. E. (1998) The sparing of extracoular muscle in dystrophinopathy is lost in mice lacking utrophin and dystrophin. J.Cell Sci. 111, 1801-1811.

Rafael, J. A., Tinsley, J. M., Potter, A. C., Deconinck, A. E. & Davies, K. E. (1998) Skeletal muscle-specific expression of a utrophin transgene rescues utrophin-dystrophin deficient mice. Nature Genetics. 19, 79-82.

Tinsley, J., Deconinck, N., Fisher, R., Kahn, D., Phelps, S., Gillis, J.-M. & Davies, K. (1998) Expression of full-length utrophin prevents muscular dystrophy in mdx mice. Nature medicine. 4, 1441-1444.

Tommasi di Vigano, A., Di Zenzo, G., Sudol, M., Cesareni, G. & Dente, L. (2000) Contribultion of the different modules in the utrophin carboxy-terminal region to the formation and regulation of the DAP complex. FEBS letters.

Winder, S. J. (1996) Structure-function relationships in dystrophin and utrophin. Biochem.Soc.Trans. 24, 497-501.

Winder, S. J. (1997) The membrane-cytoskeleton interface: the role of dystrophin and utrophin. J.Muscle Res.Cell Mot. 18, 617-629.

Winder, S. J., Gibson, T. J. & Kendrick-Jones, J. (1995) Dystrophin and utrophin: the missing links! FEBS letters. 369, 27-33.

Winder, S. J., Gibson, T. J. & Kendrick-Jones, J. (1996) Low probability of dystrophin and utrophin coiled coil regions forming dimers. Biochem.Soc.Trans. 24, 280S.

Winder, S. J., Hemmings, L., Maciver, S. K., Bolton, S. J., Tinsley, J. M., Davies, K. E., Critchley, D. R. & Kendrick-Jones, J. (1995) Utrophin actin binding domain: analysis of actin binding and cellular targeting. J. Cell Sci. 108, 63-71.

Winder, S. J. & Kendrick-Jones, J. (1995) Calcium/calmodulin-dependent regulation of the NH2-terminal F-actin binding domain of utrophin. FEBS Letters. 357, 125-128.

 
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