Dystrobrevin recruits Grb2 and α-catulin to organize neurotransmitter receptors at the neuromuscular junction

Abstract

Neuromuscular junctions (NMJs), the synapses made by motor neurons on muscle fibers, form during embryonic development, but undergo substantial remodeling postnatally. Several lines of evidence suggest that α-dystrobrevin (αDB), a component of the dystrophin-associated glycoprotein complex (DGC), is a critical regulator of the remodeling process and that tyrosine phosphorylation of one isoform, αDB-1, is required for its function at synapses. We identified a functionally important phosphorylation site on αDB-1, generated phospho-specific antibodies to it, and used them to demonstrate dramatic increases in phosphorylation during the remodeling period as well as nerve-dependent regulation in adults. We then identified proteins that bind to this site in a phospho-dependent manner, and others that bind αDB-1 phospho–independently. They include multiple members of the DGC as well as α-catulin, liprin-α1, Usp9x, PI3K, Arhgef5, and Grb2. Finally, we show that two interactors, α-catulin (phospho-independent) and Grb2 (phospho-dependent) are localized to NMJs in vivo and required for proper organization of neurotransmitter receptors on myotubes.