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J. Cell Biol.,
Volume 145, Number 2, April 19, 1999 391-402
Department of Cell and Molecular Physiology and Curriculum in Neurobiology, University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-7545
Membrane scaffolding complexes are key
features of many cell types, serving as specialized links
between the extracellular matrix and the actin cytoskeleton. An important scaffold in skeletal muscle is the
dystrophin-associated protein complex. One of the proteins bound directly to dystrophin is syntrophin, a modular protein comprised entirely of interaction motifs, including PDZ (protein domain named for PSD-95, discs
large, ZO-1) and pleckstrin homology (PH) domains. In
skeletal muscle, the syntrophin PDZ domain recruits
sodium channels and signaling molecules, such as neuronal nitric oxide synthase, to the dystrophin complex. In epithelia, we identified a variation of the dystrophin
complex, in which syntrophin, and the dystrophin homologues, utrophin and dystrobrevin, are restricted to
the basolateral membrane. We used exogenously expressed green fluorescent protein (GFP)-tagged fusion proteins to determine which domains of syntrophin are
responsible for its polarized localization. GFP-tagged
full-length syntrophin targeted to the basolateral membrane, but individual domains remained in the cytoplasm. In contrast, the second PH domain tandemly
linked to a highly conserved, COOH-terminal region
was sufficient for basolateral membrane targeting and
association with utrophin. The results suggest an interaction between syntrophin and utrophin that leaves the
PDZ domain of syntrophin available to recruit additional proteins to the epithelial basolateral membrane.
The assembly of multiprotein signaling complexes at
sites of membrane specialization may be a widespread
function of dystrophin-related protein complexes.
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