Fuzzy supertertiary interactions within PSD-95 enable ligand binding
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 domain...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2022-09-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/77242 |
| _version_ | 1811340709577359360 |
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| author | George L Hamilton Nabanita Saikia Sujit Basak Franceine S Welcome Fang Wu Jakub Kubiak Changcheng Zhang Yan Hao Claus AM Seidel Feng Ding Hugo Sanabria Mark E Bowen |
| author_facet | George L Hamilton Nabanita Saikia Sujit Basak Franceine S Welcome Fang Wu Jakub Kubiak Changcheng Zhang Yan Hao Claus AM Seidel Feng Ding Hugo Sanabria Mark E Bowen |
| author_sort | George L Hamilton |
| collection | DOAJ |
| description | 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 Förster resonance energy transfer (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. |
| first_indexed | 2024-04-13T18:46:58Z |
| format | Article |
| id | doaj.art-253718a2b64044b084b1faac60a77f9a |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-13T18:46:58Z |
| publishDate | 2022-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-253718a2b64044b084b1faac60a77f9a2022-12-22T02:34:34ZengeLife Sciences Publications LtdeLife2050-084X2022-09-011110.7554/eLife.77242Fuzzy supertertiary interactions within PSD-95 enable ligand bindingGeorge L Hamilton0https://orcid.org/0000-0002-2519-3641Nabanita Saikia1Sujit Basak2Franceine S Welcome3Fang Wu4Jakub Kubiak5Changcheng Zhang6Yan Hao7Claus AM Seidel8https://orcid.org/0000-0002-5171-149XFeng Ding9https://orcid.org/0000-0003-1850-6336Hugo Sanabria10https://orcid.org/0000-0001-7068-6827Mark E Bowen11https://orcid.org/0000-0002-9525-6986Department of Physics and Astronomy, Clemson University, Clemson, United StatesDepartment of Physics and Astronomy, Clemson University, Clemson, United StatesDepartment of Physiology and Biophysics, Stony Brook University, Stony Brook, United StatesDepartment of Physiology and Biophysics, Stony Brook University, Stony Brook, United StatesDepartment of Physiology and Biophysics, Stony Brook University, Stony Brook, United StatesMolecular Physical Chemistry, Heinrich Heine University, Düsseldorf, GermanyDepartment of Physiology and Biophysics, Stony Brook University, Stony Brook, United StatesDepartment of Physiology and Biophysics, Stony Brook University, Stony Brook, United StatesMolecular Physical Chemistry, Heinrich Heine University, Düsseldorf, GermanyDepartment of Physics and Astronomy, Clemson University, Clemson, United StatesDepartment of Physics and Astronomy, Clemson University, Clemson, United StatesDepartment of Physiology and Biophysics, Stony Brook University, Stony Brook, United StatesThe 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 Förster resonance energy transfer (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.https://elifesciences.org/articles/77242protein dynamicssingle molecule fluorescencepostsynaptic densityFRETdiscrete molecular dynamics simulations |
| spellingShingle | George L Hamilton Nabanita Saikia Sujit Basak Franceine S Welcome Fang Wu Jakub Kubiak Changcheng Zhang Yan Hao Claus AM Seidel Feng Ding Hugo Sanabria Mark E Bowen Fuzzy supertertiary interactions within PSD-95 enable ligand binding eLife protein dynamics single molecule fluorescence postsynaptic density FRET discrete molecular dynamics simulations |
| title | Fuzzy supertertiary interactions within PSD-95 enable ligand binding |
| title_full | Fuzzy supertertiary interactions within PSD-95 enable ligand binding |
| title_fullStr | Fuzzy supertertiary interactions within PSD-95 enable ligand binding |
| title_full_unstemmed | Fuzzy supertertiary interactions within PSD-95 enable ligand binding |
| title_short | Fuzzy supertertiary interactions within PSD-95 enable ligand binding |
| title_sort | fuzzy supertertiary interactions within psd 95 enable ligand binding |
| topic | protein dynamics single molecule fluorescence postsynaptic density FRET discrete molecular dynamics simulations |
| url | https://elifesciences.org/articles/77242 |
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