How does the complicated physiological system arise from molecular interactions? This is the question our lab has been pursuing for nearly two decades.

Excitatory synapses convey the majority of excitatory synaptic transmission in the central nervous system. A huge protein complex called postsynaptic density (PSD) dwells on the postsynaptic compartment of excitatory synapse in responsible for signal receiving. Elucidations of the molecular mechanisms of PSD protein interaction, organization and regulation are crucial for understanding synaptic development, signaling transmission and plasticity.

Shank and SAPAP are two highly abundant PSD scaffolding proteins that directly interact with each other to regulate excitatory synapse development and plasticity. Mutations of SAPAP, but not ot...[ Read more ]

How does the complicated physiological system arise from molecular interactions? This is the question our lab has been pursuing for nearly two decades.

Excitatory synapses convey the majority of excitatory synaptic transmission in the central nervous system. A huge protein complex called postsynaptic density (PSD) dwells on the postsynaptic compartment of excitatory synapse in responsible for signal receiving. Elucidations of the molecular mechanisms of PSD protein interaction, organization and regulation are crucial for understanding synaptic development, signaling transmission and plasticity.

Shank and SAPAP are two highly abundant PSD scaffolding proteins that directly interact with each other to regulate excitatory synapse development and plasticity. Mutations of SAPAP, but not other reported Shank PDZ domain binders, share a significant overlap on behavioral abnormalities with the mutations of Shank both in patients and animal models. However, the molecular mechanism governing the exquisite specificity of the Shank/SAPAP interaction is not clear. In the first part of my thesis work, we discover that a sequence proceeding the canonical PDZ domain of Shank, together with the elongated PDZ BC-loop, form another binding site for a sequence upstream of the SAPAP PDZ binding motif (PBM), leading to several hundred folds affinity increase of the Shank/SAPAP interaction. We provide evidence that the specific interaction afforded by this newly identified site is required for Shank synaptic targeting and Shank-induced synaptic activity increase. Our study provides a molecular explanation on how Shank and SAPAP dosage changes due to their gene copy number variations can contribute to different psychiatric disorders.