(The) shank family of synaptic scaffold proteins mediates synaptic targeting of the Rho-type guanine nucleotide exchange factor βPIX

Abstract

The Shank/ProSAP family of multidomain proteins is known to play an important role in organizing synaptic proteins at the postsynaptic density (PSD). Here I study a novel mechanism by which Shank recruits various signaling molecules to synaptic sites. Shank directly interacts with the Rho-type guanine nucleotide exchange factor (Rho-GEF) βPIX. The association between the leucine zipper (LZ) domain and the C-terminus region of βPIX and the PDZ domain of Shank mediates the interaction. Since PDZ interactions have been well characterized, it is not surprising that C-terminus region of βPIX, which contains class I PDZ binding motif, is responsible for its interaction with Shank. Still, it is very interesting that the LZ domain also binds to the PDZ domain of Shank, although the C-terminus of βPIX seems to be more essential to the interaction with Shank. Shank colocalizes with βPIX in cultured neurons. Shank forms a complex with βPIX and βPIX -associated signaling molecules including p21-associated kinase (PAK) and GIT in brain. Importantly, overexpression of Shank in cultured neurons greatly increases the synaptic localization of βPIX and PAK. These results suggest that Shank regulates the synaptic targeting of βPIX and βPIX -associated signaling proteins through its interaction with βPIX.