β-Dystrobrevin interacts directly with kinesin heavy chain in brain

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Abstract
β-Dystrobrevin, a member of the dystrobrevin protein family, is a dystrophin-related and -associated protein restricted to non-muscle tissues and is highly expressed in kidney, liver and brain. Dystrobrevins are now thought to play an important role in intracellular signal transduction, in addition to providing a membrane scaffold in muscle, but the precise role of β-dystrobrevin has not yet been determined. To study β-dystrobrevin's function in brain, we used the yeast two-hybrid approach to look for interacting proteins. Four overlapping clones were identified that encoded Kif5A, a neuronal member of the Kif5 family of proteins that consists of the heavy chains of conventional kinesin. A direct interaction of β-dystrobrevin with Kif5A was confirmed by in vitro and in vivo association assays. Co-immunoprecipitation with a monoclonal kinesin heavy chain antibody precipitated both α- and β-dystrobrevin, indicating that this interaction is not restricted to the β-dystrobrevin isoform. The site for Kif5A binding to β-dystrobrevin was localized in a carboxyl-terminal region that seems to be important in heavy chain-mediated kinesin interactions and is highly homologous in all three Kif5 isoforms, Kif5A, Kif5B and Kif5C. Pull-down and immunofluorescence experiments also showed a direct interaction between β-dystrobrevin and Kif5B. Our findings suggest a novel function for dystrobrevin as a motor protein receptor that might play a major role in the transport of components of the dystrophin-associated protein complex to specific sites in the cell.