Journal Article

Ligand binding to the PDZ domains of postsynaptic density protein 95

Angelo Toto, Søren W. Pedersen, O. Andreas Karlsson, Griffin E. Moran, Eva Andersson, Celestine N. Chi, Kristian Strømgaard, Stefano Gianni and Per Jemth

in Protein Engineering, Design and Selection

Volume 29, issue 5, pages 169-175
Published in print May 2016 | ISSN: 1741-0126
Published online March 2016 | e-ISSN: 1741-0134 | DOI:
Ligand binding to the PDZ domains of postsynaptic density protein 95

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Cellular scaffolding and signalling is generally governed by multidomain proteins, where each domain has a particular function. Postsynaptic density protein 95 (PSD-95) is involved in synapse formation and is a typical example of such a multidomain protein. Protein–protein interactions of PSD-95 are well studied and include the following three protein ligands: (i) N-methyl-d-aspartate-type ionotropic glutamate receptor subunit GluN2B, (ii) neuronal nitric oxide synthase and (iii) cysteine-rich protein (CRIPT), all of which bind to one or more of the three PDZ domains in PSD-95. While interactions for individual PDZ domains of PSD-95 have been well studied, less is known about the influence of neighbouring domains on the function of the respective individual domain. We therefore performed a systematic study on the ligand-binding kinetics of PSD-95 using constructs of different size for PSD-95 and its ligands. Regarding the canonical peptide-binding pocket and relatively short peptides (up to 15-mer), the PDZ domains in PSD-95 by and large work as individual binding modules. However, in agreement with previous studies, residues outside of the canonical binding pocket modulate the affinity of the ligands. In particular, the dissociation of the 101 amino acid CRIPT from PSD-95 is slowed down at least 10-fold for full-length PSD-95 when compared with the individual PDZ3 domain.

Keywords: CRIPT; GluN2B; Kinetics; PDZ domain; PSD-95

Journal Article.  5018 words.  Illustrated.

Subjects: Proteins

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