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Fuzzy supertertiary interactions within PSD-95 enable ligand binding
George L Hamilton1, Nabanita Saikia1, Sujit Basak2
1Department of Physics and Astronomy, Clemson University, Clemson, United States.
Elife
|September 7, 2022
Summary
The scaffold protein PSD-95
Area of Science:
- Neuroscience
- Molecular Biology
- Structural Biology
Background:
- PSD-95 is a crucial scaffold protein in synaptic plasticity.
- Its activity is regulated by interdomain interactions within the PSG supramodule.
- Flexible linkers allow for a dynamic supertertiary structure.
Purpose of the Study:
- To characterize the structure and dynamics of the PSD-95 PSG supramodule.
- To understand how the supertertiary context of PDZ3 influences synaptic protein interactions.
- To investigate the binding of neuroligin to PSD-95.
Main Methods:
- Combined discrete molecular dynamics and single-molecule Förster resonance energy transfer (FRET).
- Utilized a FRET network to measure distances in full-length PSD-95.
- Employed disulfide mapping to confirm conformational sampling.
Main Results:
- Characterized the PSG supramodule with picosecond to second time resolution.
- Identified two conformational basins sampled by the PDZ3 domain.
- Demonstrated that full-length PSD-95 binds neuroligin effectively at physiological pH, unlike truncated PDZ3.
Conclusions:
- The supertertiary context of PDZ3 is essential for recognizing synaptic ligands like neuroligin.
- Hybrid structural models provide insights into PSD-95 function at the synapse.
- Understanding PSD-95 dynamics is key to synaptic receptor-neurotransmitter release linkage.
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