Sharpin, a Novel Postsynaptic Density Protein That Directly Interacts with the Shank Family of Proteins

The Shank family of proteins (also termed CortBP, ProSAP, or Synamon) is highly enriched in the postsynaptic density (PSD) of excitatory synapses in brain. Shank contains multiple domains for protein–protein interactions, including ankyrin repeats, SH3 domain, PDZ domain, SAM domain, and an extensive proline-rich region. We have identified a novel protein, termed Sharpin, that directly interacts with the ankyrin repeats of Shank. Sharpin is enriched in the PSD and forms a complex with Shank in heterologous cells and brain. Immunostaining reveals the presence of Sharpin at excitatory synapses and its colocalization with Shank. While the C-terminal half of Sharpin interacts with Shank, the N-terminal half of Sharpin mediates homomultimerization. Considering the fact that the ankyrin repeats and the SH3 domain of Shank can be truncated by alternative splicing, these results define Sharpin as a novel PSD protein that may regulate the complexity of the Shank-based protein network in an alternative splicing-dependent manner.