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© The Rockefeller University Press, 0021-9525/1998//1269 $5.00
The Journal of Cell Biology, Volume 142, Number 5, , 1998 1269-1278

Articles

Differential Membrane Localization and Intermolecular Associations of {alpha}-Dystrobrevin Isoforms in Skeletal Muscle



Matthew F. Peters*, Hélène M. Sadoulet-Puccio{ddagger}, R. Mark Grady§, Neal R. Kramarcy*, Louis M. Kunkel{ddagger}, Joshua R. Sanes||, Robert Sealock*, and Stanley C. Froehner*

* Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7545; {ddagger} Howard Hughes Medical Institute, Division of Genetics, The Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115; § Department of Pediatrics, and || Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110

{alpha}-Dystrobrevin is both a dystrophin homologue and a component of the dystrophin protein complex. Alternative splicing yields five forms, of which two predominate in skeletal muscle: full-length {alpha}-dystrobrevin-1 (84 kD), and COOH-terminal truncated {alpha}-dystrobrevin-2 (65 kD). Using isoform-specific antibodies, we find that {alpha}-dystrobrevin-2 is localized on the sarcolemma and at the neuromuscular synapse, where, like dystrophin, it is most concentrated in the depths of the postjunctional folds. {alpha}-Dystrobrevin-2 preferentially copurifies with dystrophin from muscle extracts. In contrast, {alpha}-dystrobrevin-1 is more highly restricted to the synapse, like the dystrophin homologue utrophin, and preferentially copurifies with utrophin. In yeast two-hybrid experiments and coimmunoprecipitation of in vitro–translated proteins, {alpha}-dystrobrevin-2 binds dystrophin, whereas {alpha}-dystrobrevin-1 binds both dystrophin and utrophin. {alpha}-Dystrobrevin-2 was lost from the nonsynaptic sarcolemma of dystrophin-deficient mdx mice, but was retained on the perisynaptic sarcolemma even in mice lacking both utrophin and dystrophin. In contrast, {alpha}-dystrobrevin-1 remained synaptically localized in mdx and utrophin-negative muscle, but was absent in double mutants. Thus, the distinct distributions of {alpha}-dystrobrevin-1 and -2 can be partly explained by specific associations with utrophin and dystrophin, but other factors are also involved. These results show that alternative splicing confers distinct properties of association on the {alpha}-dystrobrevins.

Key Words: dystrophin complex • neuromuscular junction • postsynaptic folds • high revolution immunofluorescence • isoform-specific antibodies

Abbreviations used in this paper: Ab, polyclonal antibody; AChR, acetylcholine receptor; CR, cysteine rich; CT, COOH-terminal; DRP, dystrophin-related protein; DUR, dystrobrevin-unique region; NMJ, neuromuscular junction; PDZ, protein domain originally identified in postsynaptic density-95, discs large, ZO-1; {alpha}-BgTx, {alpha}-bungarotoxin.

Address all correspondence to S.C. Froehner, Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7545. Tel.: (919) 966-1239. Fax: (919) 966-6413. E-mail: froehner{at}med.unc.edu


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