The structural flexibility of the shank1 PDZ domain is important for its binding to different ligands

Shank is a dose-dependent regulator of Cav1 calcium current and CREB target expression

“…The SHN-1 protein lacks an SH3 domain but has all other domains found in mammalian Shank proteins (Figure 1A). Many protein ligands have been identified for the Shank PDZ domain (Lee et al, 2011). Of these potential binding partners, we focused on EGL-19/Ca v 1 because human CACNA1C (which encodes a Ca v 1 α-subunit) is mutated in Timothy Syndrome (TS), a rare monogenic form of ASD (Splawski et al, 2005, 2004), and polymorphisms linked to CACNA1C are associated with multiple psychiatric disorders (Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013).…”

“…For example, increased and decreased expression of the yeast histones H2A and H2B results in similar loss of function phenotypes (chromosome loss and altered gene expression) (Clark-Adams et al, 1988; Meeks-Wagner and Hartwell, 1986). Shank binds many other synaptic proteins (Lee et al, 2011; Sakai et al, 2011) and undergoes zinc induced polymerization into large complexes (Baron et al, 2006; Hayashi et al, 2009). Thus, increased and decreased Shank abundance could disrupt the stoichiometry of post-synaptic complexes.…”

“…Because Shank is highly enriched in the post-synaptic densities of excitatory synapses, prior studies have focused on the idea that Shank proteins regulate some aspect of synapse formation or function. Through its various domains, Shank proteins bind hundreds of other synaptic proteins (Lee et al, 2011; Sakai et al, 2011) thereby potentially altering diverse cellular functions. Shank proteins have been implicated in synaptic transmission, synapse formation, synaptic plasticity, and cytoskeletal remodeling (Jiang and Ehlers, 2013).…”

Solution structures of the SH3 domains from Shank scaffold proteins and their interactions with Cav1.3 calcium channels

“…The binding between Shank and Cav1.3 has been shown to arise from a two‐point interaction which involves both the SH3 and the PDZ domains . Although it is clear that the PDZ domain from Shank interacts with the class I PDZ binding motif that is located at the C‐terminal end of Cav1.3 , the specific binding site for the SH3 domain remains to be determined and hence we have also investigated the interactions of the Shank SH3 domains with the C‐terminal proline‐rich region of Cav1.3.…”

“…The binding between Shank and Cav1.3 has been shown to arise from a two-point interaction which involves both the SH3 and the PDZ domains [24]. Although it is clear that the PDZ domain from Shank interacts with the class I PDZ binding motif that is located at the C-terminal end of Cav1.3 [24,31], the specific binding site for the SH3 domain remains to be determined and hence we have also investigated the interactions of the Shank SH3 domains with the C-terminal proline-rich region of Cav1.3. Amino acid sequence alignment of human Shank SH3 domains with the SH3 domains from human RIM-binding protein 2 (O15034), cacophony RIM-binding protein (A0A0B4JDC9), yeast Nbp2 (Q12163), mouse c-Crk (Q64010), yeast Myosin-5 (Q04439), and human Abl (P00519).…”