Structural basis for PDZ domain interactions in the post-synaptic density scaffolding protein Shank3

Journal of Neurochemistry
Srinivas Kumar PonnaPetri Kursula

Abstract

The Shank proteins are crucial scaffolding elements of the post-synaptic density (PSD). One of the best-characterized domains in Shank is the PDZ domain, which binds to C-terminal segments of several other PSD proteins. We carried out a detailed structural analysis of Shank3 PDZ domain-peptide complexes, to understand determinants of binding affinity towards different ligand proteins. Ligand peptides from four different proteins were cocrystallized with the Shank3 PDZ domain, and binding affinities were determined calorimetrically. In addition to conserved class I interactions between the first and third C-terminal peptide residue and Shank3, side chain interactions of other residues in the peptide with the PDZ domain are important factors in defining affinity. Structural conservation suggests that the binding specificities of the PDZ domains from different Shanks are similar. Two conserved buried water molecules in PDZ domains may affect correct local folding of ligand recognition determinants. The solution structure of a tandem Shank3 construct containing the SH3 and PDZ domains showed that the two domains are close to each other, which could be of relevance, when recognizing and binding full target proteins. The SH3 domain d...Continue Reading

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Citations

Apr 22, 2020·Advanced Therapeutics·Nikolaj R ChristensenKristian Strømgaard
Apr 11, 2019·Frontiers in Neuroscience·Yuri A UshkaryovNickolai V Vysokov
Mar 19, 2021·Biochemistry and Biophysics Reports·Erik I HallinPetri Kursula

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