Fig. 1

Macromolecular complexes within the interactome of SHANK3. The multiple layers of the functional units in the central nervous system are shown in succession. In the left lower corner a hippocampal pyramidal neuron is depicted. At the top an overview of a synaptic contact and a detailed illustration of the multiple connections between the different interaction domains of SHANK3 and other synaptic proteins is shown. On the right, putative macromolecular assemblies associated to cellular actin nucleation, which include SHANK3, are shown in the soma. SHANK3 localizes to the postsynaptic density (PSD). The PSD is an electron dense thickening underneath the postsynaptic membrane of glutamatergic synapses. It comprises a great multitude of proteins, which form a wide macromolecular complex. Interaction between SHANK3 and other proteins is mediated by six protein domains, which are depicted by form and color in this image: The SPN-, ANK-, SH3-, PDZ-, PRO-, and SAM-domain. A subset of SHANK3-interacting proteins is illustrated here. DLG4 (or PSD95) is also depicted by its functional domains (PDZ, SH3, GK) to emphasize that different proteins can contribute similar domains to the structural composition of the PSD. Membrane-associated guanylate kinases (MAGUKs) such as DLG4 also serve as major organizers of synapses, by forming a modular interface between the multiple layers of the PSD. For instance, DLG4, DLGAP, SHANK3 and HOMER connect GRM and NMDAR complexes. An additional connection of this complex to the cytoskeleton is mediated by SHANK3’s interaction with CTTN, SHARPIN, SPTAN1, and other proteins. Depending on its configuration, the SPN-domain prevents the binding of SPTAN1 to the ANK-domain. The ARP2/3-complex is crucial for actin nucleation and polymerization. By its interaction with the WAVE regulatory complex (WRC), components of the RAC1-pathway, and ARPC2 itself, SHANK3 might mediate their influence on actin dynamics. PSD: Postsynaptic density, SHANK: SH3 and multiple ankyrin repeat domains, SPN: SHANK/ProSAP/N-terminal, SH3: Src homology 3, PDZ: PSD95/DlgA/Zo-1, PRO: Proline-rich, SAM: Sterile alpha motif, ANK: Ankyrin repeats