At excitatory synapses, members of the membrane-associated guanylate kinase (MAGUK) protein family provide some of the scaffolding that links ionotropic glutamate receptors to downstream signaling molecules. MAGUK proteins are composed of one or three PDZ domains, a Src-Homology 3 (SH3) domain, and a domain homologous to guanylate kinase (GK). The PDZ domains of neuronal MAGUK proteins mediate protein-protein interactions with ion channels, receptors and components of second messenger cascades, thereby promoting rapid and efficient synaptic transmission. Interaction partners for the SH3 and GK domains have also been identified; however, the molecular mechanisms for regulating PSD-95 function through these interactions are unclear. Recently, we have crystallized the SH3GK module of PSD-95 and determined its three dimensional structure by X-ray diffraction. The goal of this proposal is to determine how the structural features of the SH3GK complex relate to these SH3GK interactions and evaluate how these interactions contribute to PSD-95 function, including synaptic delivery of PSD-95, synapse maturation and ion channel clustering.
