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.
Metrics
-
- 1,419
- views
-
- 356
- downloads
-
- 18
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Fuzzy supertertiary interactions within PSD-95 enable ligand binding
eLife 11:e77242.
https://doi.org/10.7554/eLife.77242
Further reading
-
- Neuroscience
The vestibular system is integral to behavior; the loss of peripheral vestibular function leads to disabling consequences, such as blurred vision, dizziness, and unstable posture, severely limiting activities of daily living. Fortunately, the vestibular system’s well-defined peripheral structure and well-understood encoding strategies offer unique opportunities for developing sensory prostheses to restore vestibular function. While these devices show promising results in both animal models and implanted patients, substantial room for improvement remains. Research from an engineering perspective has largely focused on optimizing stimulation protocol to improve outcomes. However, this approach has often been pursued in isolation from research in neuroscience that has enriched our understanding of neural responses at the synaptic, cellular, and circuit levels. Accordingly, this review bridges the domains of neuroscience and engineering to consider recent progress and challenges in vestibular prosthesis development. We advocate for interdisciplinary approaches that leverage studies of neural circuits at the population level, especially in light of recent advancement in large-scale recording technology, to identify impediments still to overcome and to develop more naturalistic stimulation strategies. Fully integrating neuroscience and engineering in the context of prosthesis development will help advance the field forward and ultimately improve patient outcomes.
-
- Neuroscience
Hearing involves analyzing the physical attributes of sounds and integrating the results of this analysis with other sensory, cognitive, and motor variables in order to guide adaptive behavior. The auditory cortex is considered crucial for the integration of acoustic and contextual information and is thought to share the resulting representations with subcortical auditory structures via its vast descending projections. By imaging cellular activity in the corticorecipient shell of the inferior colliculus of mice engaged in a sound detection task, we show that the majority of neurons encode information beyond the physical attributes of the stimulus and that the animals’ behavior can be decoded from the activity of those neurons with a high degree of accuracy. Surprisingly, this was also the case in mice in which auditory cortical input to the midbrain had been removed by bilateral cortical lesions. This illustrates that subcortical auditory structures have access to a wealth of non-acoustic information and can, independently of the auditory cortex, carry much richer neural representations than previously thought.
