LIFS researchers reveal mechanism governing AMPAR synaptic targeting and clustering
Prof. Mingjie Zhang and his team reported that stargazin uses its entire C-terminal tail bind PSD-95 (Postsynaptic density protein 95) via a specific and multivalent interaction mode. Their findings, published in Neuron, reveal the mechanism of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor synaptic trafficking and transmission at the neuronal synapses.
Targeting, clustering, and dynamic retention of AMPA receptors (AMPARs) to postsynaptic densities (PSDs) require a group of scaffold proteins known as the disc-large (DLG) subfamily of membrane-associated guanylate kinases (MAGUKs). Interestingly, PSD-95 does not directly bind to AMPAR subunits. Instead, the association is mediated by a group of AMPAR auxiliary subunits termed transmembrane AMPAR regulatory proteins (TARPs). Despite extensive studies, the molecular mechanism governing specific TARP/MAGUK interaction remains elusive.
Using stargazin, the first TARP protein identified, and PSD-95 as the representatives, the research team revealed the mode of interaction between these two proteins. Specifically, the entire tail of stargazin binds to PSD-95 with high affinity and specificity, and the stargazin/PSD-95 complex form condensed assembly via phase separation at physiological protein concentrations. Also, other TARPs and MAGUKs interact with each other in a similar fashion.
Several studies in the past identified that the Arg (arginine)-rich motif of TARPs is important for AMPAR synaptic targeting. Therefore, the researcher team further demonstrated that mutations in the Arg-rich motif weaken TARP’s condensation with PSD-95 and impair TARP-mediated AMPAR synaptic transmission in mice hippocampal neurons.
These findings identify the interaction mode between TARP and MAGUK and provide long-sought insight into understanding the clustering of other synaptic transmembrane proteins.
Zeng M, Díaz-Alonso J, Ye F, Chen X, Xu J, Ji Z, Nicoll RA, Zhang M. Phase Separation-Mediated TARP/MAGUK Complex Condensation and AMPA Receptor Synaptic Transmission. Neuron. 2019 Nov 6;104(3):529-543.e6. doi: 10.1016/j.neuron.2019.08.001.