Molecular basis of interactions between CaMKII and α-actinin-2 that underlie dendritic spine enlargement
- University College London, United Kingdom
Abstract
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is essential for long-term potentiation (LTP) of excitatory synapses that is linked to learning and memory. In this study, we focused on understanding how interactions between CaMKIIα and the actin crosslinking protein α-actinin-2 underlie long-lasting changes in dendritic spine architecture. We found that association of the two proteins was unexpectedly elevated within two minutes of NMDA receptor stimulation that triggers structural LTP in primary hippocampal neurons. Furthermore, disruption of interactions between the two proteins prevented the accumulation of enlarged mushroom-type dendritic spines following NMDA receptor activation. α-actinin-2 binds to the regulatory segment of CaMKII. Calorimetry experiments, and a crystal structure of α-actinin-2 EF hands 3 and 4 in complex with the CaMKII regulatory segment, indicate that the regulatory segment of autoinhibited CaMKII is not fully accessible to α-actinin-2. Pull-down experiments show that occupation of the CaMKII substrate binding groove by GluN2B markedly increases α-actinin-2 access to the CaMKII regulatory segment. Furthermore, in situ labelling experiments are consistent with the notion that recruitment of CaMKII to NMDA receptors contributes to elevated interactions between the kinase and α-actinin-2 during structural LTP. Overall, our study provides new mechanistic insight into the molecular basis of structural LTP and reveals an added layer of sophistication to the function of CaMKII.
Data availability
Coordinates and structure factors have been deposited with the RCSB Protein Databank for the EF3-4 - CaMKII regulatory segment peptide complex with accession ID 6TS3.
Article and author information
Author details
Funding
Wellcome Trust (104194/Z/14/Z)
- Matthew G Gold
Biotechnology and Biological Sciences Research Council (BB/N015274/1)
- Jian Zhu
- Christopher J Penny
- Matthew G Gold
Biotechnology and Biological Sciences Research Council (2081382)
- Ashton J Curtis
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Takeo Saneyoshi, Kyoto University, Japan
Ethics
Animal experimentation: Experiments involving rats were performed in accordance with the United Kingdom Animals Act, 1986 and within University College London Animal Research guidelines overseen by the UCL Animal Welfare and Ethical Review Body under project code 14058.
Version history
- Received: November 18, 2022
- Preprint posted: December 5, 2022 (view preprint)
- Accepted: July 24, 2023
- Accepted Manuscript published: July 25, 2023 (version 1)
- Accepted Manuscript updated: July 28, 2023 (version 2)
- Version of Record published: September 7, 2023 (version 3)
Copyright
© 2023, Curtis 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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Molecular basis of interactions between CaMKII and α-actinin-2 that underlie dendritic spine enlargement
eLife 12:e85008.
https://doi.org/10.7554/eLife.85008
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