[gamma]-Syntrophin scaffolding is spatially and functionally distinct from that of the [alpha]/[beta] syntrophins

The syntrophins are a family of scaffolding proteins with multiple protein interaction domains that link signaling proteins to dystrophin family members. Each of the three most characterized syntrophins ([alpha], [beta]1, [beta]2) contains a PDZ domain that binds a unique set of signaling proteins including kinases, ion and water channels, and neuronal nitric oxide synthase (nNOS). The PDZ domains of the [gamma]-syntrophins do not bind nNOS. In vitro pull-down assays show that the [gamma]-syntrophins can bind dystrophin but have unique preferences for the syntrophin binding sites of dystrophin family members. Despite their ability to bind dystrophin in vitro, neither [gamma]-syntrophin isoform co-localizes with dystrophin in skeletal muscle. Furthermore, [gamma]-syntrophins do not co-purify with dystrophin isolated from mouse tissue. These data suggest that the interaction of [gamma]-syntrophin with dystrophin is transient and potentially subject to regulatory mechanisms. [gamma]1-Syntrophin is highly expressed in brain and is specifically localized in hippocampal pyramidal neurons, Purkinje neurons in cerebellum, and cortical neurons. [gamma]2-Syntrophin is expressed in many tissues including skeletal muscle where it is found only in the subsynaptic space beneath the neuromuscular junction. In both neurons and muscle, [gamma]-syntrophin isoforms localize to the endoplasmic reticulum where they may form a scaffold for signaling and trafficking. [PUBLICATION ABSTRACT]