PSD proteins

We are investigating the biology and function of members of the PSD95-MAGUK family of scaffolding proteins, which are critical for the proper trafficking and retention of glutamate receptors at synaptic sites. As such, PSD95-MAGUK proteins are important for excitatory neurotransmission and are implicated in excitotoxicity and neuronal disease. We generated a novel research tool (an intramolecular FRET probe) that allowed us to detect and measure changes in PSD95-MAGUK conformation in vivo. Use of this probe demonstrated that two members of the family, SAP97 and PSD95, exist in extended and compact conformations which govern interactions with different glutamate receptor subtypes, and identify the N-terminal domain as a critically important locus for eliciting dynamic changes in PSD95-MAGUK conformation and function. Much less is known about what regulates the synaptic localization and function of a third member of the PSD95-MAGUK family, SAP102.

It was reported almost two decades ago that SAP102 possessed a canonical zinc-binding domain at its N-terminus, but its utility or function in vivo remains unknown. Using the tools and molecular reagents we have generated, we will characterize zinc-induced changes in SAP102 synaptic turnover, localization, and interactions with glutamate receptor subtypes. These experiments will provide novel molecular detail on SAP102 synaptic function and will advance research on zinc-dependent signaling mechanisms at excitatory synapses.  Members of the PSD95-MAGUK family of proteins are current candidates for rational drug design efforts aimed at developing new therapies for psychiatric and neurodegenerative diseases. Our research findings may provide critical structural information that will aid these strategies.