PSD proteins

Our lab investigates the biology and function of the PSD95-MAGUK family of scaffolding proteins, which are essential for the trafficking and synaptic retention of glutamate receptors. These proteins play a central role in excitatory neurotransmission and are implicated in excitotoxicity and various neurological diseases.

We developed a novel intramolecular, FRET-based biosensor that enables the detection of conformational changes in PSD95-MAGUK proteins in vivo. Using this tool, we discovered that two members of the family, SAP97 and PSD95, can adopt both extended and compact conformations. These conformations influence their interactions with different glutamate receptor subtypes, and our data highlight the N-terminal domain as a key regulatory region governing these dynamic structural states.

In contrast, much less is known about the third major PSD95-MAGUK protein, SAP102, particularly regarding its synaptic regulation. Although SAP102 was reported nearly two decades ago to possess a canonical zinc-binding domain at its N-terminus, its in vivo function remains unclear. Using our molecular tools, we are investigating how zinc signaling influences SAP102 turnover, localization, and receptor interactions at synapses. These studies aim to reveal new molecular mechanisms underlying zinc-dependent modulation of synaptic function.

Given their central roles in synaptic organization and plasticity, PSD95-MAGUK proteins are promising targets for therapeutic intervention in psychiatric and neurodegenerative disorders. Our work may provide foundational structural insights to support rational drug design strategies targeting these scaffolds.