Supertertiary Structure of the MAGUK Core from PSD-95

• DOI: 10.1016/j.str.2012.12.014
• Publication Date: 2013-02-07T16:45:17Z
• Authors: Jun Zhang; Steven M. Lewis; Brian Kuhlman; Andrew L. Lee
• Keywords: 0303 health sciences; Binding Sites; Molecular Sequence Data; Intracellular Signaling Peptides and Proteins; Membrane Proteins; PDZ Domains; Molecular Dynamics Simulation; Crystallography, X-Ray; Protein Structure, Secondary; Recombinant Proteins; Rats; 03 medical and health sciences; Structural Biology; Mutation; Escherichia coli; Animals; Amino Acid Sequence; Phosphorylation; Protein Structure, Quaternary; Molecular Biology; Disks Large Homolog 4 Protein; Oligopeptides; Sequence Alignment; Protein Binding

The family of membrane-associated guanylate kinase (MAGUK) scaffold proteins comprises members that function at neuronal synapses, tight junctions, immunological synapses, and neutrophil membranes. Through their multiple domains, MAGUKs organize events of signal transduction, cell adhesion, and molecular trafficking. Here, we use nuclear magnetic resonance, small-angle X-ray scattering, and Rosetta modeling to reveal the structural preferences and interdomain dynamics of the MAGUK core (PDZ3-SH3-guanylate kinase) from postsynaptic density-95 (PSD-95), the best known MAUGK. PSD-95 is highly abundant in the postsynaptic density of excitatory neurons and is responsible for coupling glutamate receptors with internal postsynaptic structures. These solution-based studies show that the MAGUK core PDZ domain (PDZ3) interacts directly with the SH3 domain via its canonical peptide binding groove, with the connecting linker serving as an adhesive. This weak interaction, however, is dynamic and weakened further by PDZ3 ligands and linker phosphorylation, suggesting that domain dynamics may be central to MAGUK function.