Shank, a master scaffolding protein of postsynaptic density (PSD), plays critical roles in protein complex assembly and synaptic signal transduction in the excitatory synapses. Dysfunctions of Shank will lead to several severe mental disorders including autism or autism spectrum disorder (ASD). Recent studies have reported Shank mutant mice displayed autistic-like behaviors. Therefore, characterization of Shank should make an important contribution to our understanding of normal brain function and to develop treatments methods for mental disorders.

Shank can be clustered to PSD-95 complex by interacting with DLGAP. The interaction is not only important for Shank synaptic localization but also critical for the assembly of a ternary protein complex (PSD-95/DLGAP/Shank) which serves as...[ Read more ]

Shank, a master scaffolding protein of postsynaptic density (PSD), plays critical roles in protein complex assembly and synaptic signal transduction in the excitatory synapses. Dysfunctions of Shank will lead to several severe mental disorders including autism or autism spectrum disorder (ASD). Recent studies have reported Shank mutant mice displayed autistic-like behaviors. Therefore, characterization of Shank should make an important contribution to our understanding of normal brain function and to develop treatments methods for mental disorders.

Shank can be clustered to PSD-95 complex by interacting with DLGAP. The interaction is not only important for Shank synaptic localization but also critical for the assembly of a ternary protein complex (PSD-95/DLGAP/Shank) which serves as a master scaffolding platform in PSD. DLGAP binds to Shank PDZ domain via its C-terminal PDZ binding motif (PBM) with a relatively low binding affinity. Here, I discovered an unexpected assembly mode between DLGAP3 PBM and Shank3 PDZ domain. I demonstrated that the N-terminal extension of Shank3 PDZ domain recognizes the uptream sequence of DLGAP3 PBM. Thus, the upstream sequence of DLGAP3 PBM and the PBM synergistically bind to NPDZ of Shank3, which greatly increases the binding affinity and specificity between Shank and DLGAP. I proposed that this novel binding mode would be a general mechanism governing at least a subset of PDZ/target interaction with strong binding affinities.