Frank, RAW orcid.org/0000-0001-9724-9547, Zhu, F, Komiyama, NH et al. (1 more author) (2017) Hierarchical organization and genetically separable subfamilies of PSD95 postsynaptic supercomplexes. Journal of Neurochemistry, 142 (4). pp. 504-511. ISSN 0022-3042
Abstract
PSD95 is an abundant postsynaptic scaffold protein in glutamatergic synapses that assembles into supercomplexes composed of over 80 proteins including neurotransmitter receptors, ion channels and adhesion proteins. How these diverse constituents are organized into PSD95 supercomplexes in vivo is poorly understood. Here, we dissected the supercomplexes in mice combining endogenous gene‐tagging, targeted mutations and quantitative biochemical assays. Generating compound heterozygous mice with two different gene‐tags, one on each Psd95 allele, showed that each ~1.5 MDa PSD95‐containing supercomplex contains on average two PSD95 molecules. Gene‐tagging the endogenous GluN1 and PSD95 with identical Flag tags revealed N‐methyl D‐aspartic acid receptors (NMDARs) containing supercomplexes that represent only 3% of the total population of PSD95 supercomplexes, suggesting there are many other subtypes. To determine whether this extended population of different PSD95 supercomplexes use genetically defined mechanisms to specify their assembly, we tested the effect of five targeted mouse mutations on the assembly of known PSD95 interactors, Kir2.3, Arc, IQsec2/BRAG1 and Adam22. Unexpectedly, some mutations were highly selective, whereas others caused widespread disruption, indicating that PSD95 interacting proteins are organized hierarchically into distinct subfamilies of ~1.5 MDa supercomplexes, including a subpopulation of Kir2.3‐NMDAR ion channel‐channel supercomplexes. Kir2.3‐NMDAR ion channel‐channel supercomplexes were found to be anatomically restricted to particular brain regions. These data provide new insight into the mechanisms that govern the constituents of postsynaptic supercomplexes and the diversity of synapse types.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 19 Sep 2018 13:49 |
Last Modified: | 10 Oct 2018 13:47 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1111/jnc.14056 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:135851 |