An SH3 domain like no other at the post-synaptic density
The Shank family of proteins functions as a molecular scaffold in the neuronal post-synaptic density, enabling numerous protein-protein interactions. Shanks are large multi-domain molecules, and one of the conserved domains is an SH3 domain. Using high-resolution X-ray crystallography, we show that the SH3 domain in the Shank family has lost its canonical ligand-binding site.
Shanks are large scaffolding proteins in the post-synaptic density, which contain several protein-protein interaction domains. The latter include an SH3 and a PDZ domain; while several ligands for the PDZ domain have been identified, binding partners for the SH3 domain have remained unknown.
Together with Prof. Tobias Böckers (Ulm, Germany), we studied the SH3 domain from the Shank3 isoform using ultrahigh-resolution X-ray crystallography. The crystal structure was solved using single-wavelength anomalous dispersion with data collected at the Biocenter Oulu protein crystallography core facility, and diffraction data collected using synchrotron radiation was employed for structure refinement at 0.87-Å resolution.
The data show that while the SH3 domain in the Shank family is conserved and folded like a typical SH3 domain, its canonical peptide-binding site has been lost during evolution. The results suggest that the SH3 domain of the Shank proteins either has atypical peptide ligands or it has lost its function in protein-protein interactions.
Shanks have been linked to neuropsychiatric and neurodevelopmental diseases, such as autism spectrum disorders and schizophrenia. The work gives new insights into the structure and function of the Shank family in the post-synaptic density.
Ponna S.K., Myllykoski M., Boeckers T.M. & Kursula P. (2017) Structure of an unconventional SH3 domain from the postsynaptic density protein Shank3 at ultrahigh resolution. Biochem. Biophys. Res. Commun. 490:806-812.