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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
PubMed
Summary
This summary is machine-generated.

The scaffold protein PSD-95

Keywords:
E. coliFRETdiscrete molecular dynamics simulationsmolecular biophysicsneurosciencepostsynaptic densityprotein dynamicssingle molecule fluorescencestructural biology

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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.