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J. Cell Biol.,
Volume 142, Number 5, September 7, 1998 1269-1278
-Dystrobrevin Isoforms in Skeletal Muscle
* Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
27599-7545; 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
-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 -dystrobrevin-1 (84 kD), and COOH-terminal truncated
-dystrobrevin-2 (65 kD). Using isoform-specific antibodies, we find that -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. -Dystrobrevin-2 preferentially copurifies with dystrophin from muscle extracts.
In contrast, -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, -dystrobrevin-2
binds dystrophin, whereas -dystrobrevin-1 binds both
dystrophin and utrophin. -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, -dystrobrevin-1 remained synaptically localized in mdx and utrophin-negative muscle, but was absent in double mutants. Thus, the distinct
distributions of -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 -dystrobrevins.
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