Fuzzy supertertiary interactions within PSD-95 enable ligand binding
- Clemson University, United States
- Stony Brook University, United States
- Heinrich-Heine-University Düsseldorf, Germany
- Heinrich Heine University Düsseldorf, Germany
Abstract
The scaffold protein PSD-95 links postsynaptic receptors to sites of presynaptic neurotransmitter release. Flexible linkers between folded domains in PSD-95 enable a dynamic supertertiary structure. Interdomain interactions within the PSG supramodule, formed by PDZ3, SH3 and Guanylate Kinase domains, regulate PSD-95 activity. Here we combined Discrete Molecular Dynamics and single molecule FRET to characterize the PSG supramodule, with time resolution spanning picoseconds to seconds. We used a FRET network to measure distances in full-length PSD-95 and model the conformational ensemble. We found that PDZ3 samples two conformational basins, which we confirmed with disulfide mapping. To understand effects on activity, we measured binding of the synaptic adhesion protein neuroligin. We found that PSD-95 bound neuroligin well at physiological pH while truncated PDZ3 bound poorly. Our hybrid structural models reveal how the supertertiary context of PDZ3 enables recognition of this critical synaptic ligand.
Data availability
Datasets of FRET values from smTIRF have been uploaded as Figure 4-Source Data 1. The MATLAB scripts used to analyze smTIRF data have been uploaded as Source Code 1. Datasets from Confocal Microscopy with Multiparameter Fluorescence Detection (Raw, MFD Bursts, TCSPC, PDA, and FCS), along with structures used in generating simulated distances and DMD screening, are available at Zenodo (DOI: 10.5281/zenodo.6983428). Datasets from Discrete Molecular Dynamics are available at https://dlab.clemson.edu/research/PSD95-PSG/.
Article and author information
Author details
Funding
National Institute of Mental Health (MH081923)
- Mark E Bowen
National Institute of General Medical Sciences (GM130451)
- Hugo Sanabria
National Institute of General Medical Sciences (GM119691)
- Feng Ding
National Science Foundation (MCB1749778)
- Hugo Sanabria
National Science Foundation (CBET1553945)
- Feng Ding
European Research Council (671208)
- George L Hamilton
- Claus AM Seidel
- Hugo Sanabria
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Hamilton et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Fuzzy supertertiary interactions within PSD-95 enable ligand binding
eLife 11:e77242.
https://doi.org/10.7554/eLife.77242
Further reading
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When navigating environments with changing rules, human brain circuits flexibly adapt how and where we retain information to help us achieve our immediate goals.
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When holding visual information temporarily in working memory (WM), the neural representation of the memorandum is distributed across various cortical regions, including visual and frontal cortices. However, the role of stimulus representation in visual and frontal cortices during WM has been controversial. Here, we tested the hypothesis that stimulus representation persists in the frontal cortex to facilitate flexible control demands in WM. During functional MRI, participants flexibly switched between simple WM maintenance of visual stimulus or more complex rule-based categorization of maintained stimulus on a trial-by-trial basis. Our results demonstrated enhanced stimulus representation in the frontal cortex that tracked demands for active WM control and enhanced stimulus representation in the visual cortex that tracked demands for precise WM maintenance. This differential frontal stimulus representation traded off with the newly-generated category representation with varying control demands. Simulation using multi-module recurrent neural networks replicated human neural patterns when stimulus information was preserved for network readout. Altogether, these findings help reconcile the long-standing debate in WM research, and provide empirical and computational evidence that flexible stimulus representation in the frontal cortex during WM serves as a potential neural coding scheme to accommodate the ever-changing environment.
