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Postsynaptic targeting of alternative postsynaptic density-95 isoforms by distinct mechanisms
Dane M Chetkovich1, Robert C Bunn, Sheng-Han Kuo
1Department of Physiology, University of California, San Francisco, San Francisco, California 94143-0444, USA.
Summary
New research reveals how PSD95beta scaffolding proteins cluster at synapses. L27 domain interactions and Hrs-regulated trafficking are critical for postsynaptic protein clustering at excitatory synapses.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Postsynaptic density-95 (PSD95)/synapse-associated protein-90 (SAP90) proteins are crucial scaffolding proteins at excitatory synapses.
- These proteins regulate synaptic signaling and plasticity through modular interaction motifs like PDZ, Src homology 3, and guanylate kinase domains.
Purpose of the Study:
- To investigate the role of N-terminal alternative splicing in PSD95 function.
- To identify novel interaction partners and regulatory mechanisms for PSD95 isoforms at synapses.
Main Methods:
- Yeast two-hybrid and coimmunoprecipitation assays were used to identify protein interactions.
- Heterologous cell and hippocampal neuron transfections were performed to study protein localization and trafficking.
- The impact of disrupting Hrs-regulated endosomal sorting on PSD95beta clustering was examined.
Main Results:
- A novel PSD95 isoform, PSD95beta, containing an L27 motif, was identified.
- The L27 domain of PSD95beta interacts with L27 domains in MAGUK kinases and Hrs.
- L27 domain interactions and Hrs-regulated vesicular trafficking are essential for PSD95beta synaptic clustering, distinct from PSD95alpha trafficking.
Conclusions:
- PSD95beta exhibits molecular and functional heterogeneity within synaptic PSD95 complexes.
- L27 domain interactions and Hrs-mediated endosomal sorting play critical roles in postsynaptic protein clustering.
- This study elucidates novel mechanisms governing synaptic organization and plasticity.