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Published on: August 15, 2017
Multivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density
Zheng Shen1, Daxiao Sun2, Adriana Savastano1
1German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075, Göttingen, Germany.
Abstract:
Alzheimer's disease begins with mild memory loss and slowly destroys memory and thinking. Cognitive impairment in Alzheimer's disease has been associated with the localization of the microtubule-associated protein Tau at the postsynapse. However, the correlation between Tau at the postsynapse and synaptic dysfunction remains unclear. Here, we show that Tau arrests liquid-like droplets formed by the four postsynaptic density proteins PSD-95, GKAP, Shank, Homer in solution, as well as NMDA (N-methyl-D-aspartate)-receptor-associated protein clusters on synthetic membranes. Tau-mediated condensate/cluster arrest critically depends on the binding of multiple interaction motifs of Tau to a canonical GMP-binding pocket in the guanylate kinase domain of PSD-95. We further reveal that competitive binding of a high-affinity phosphorylated peptide to PSD-95 rescues the diffusional dynamics of an NMDA truncated construct, which contains the last five amino acids of the NMDA receptor subunit NR2B fused to the C-terminus of the tetrameric GCN4 coiled-coil domain, in postsynaptic density-like condensates/clusters. Taken together, our findings propose a molecular mechanism where Tau modulates the dynamic properties of the postsynaptic density.
Insights
Microtubule-associated protein Tau arrests postsynaptic protein clusters, contributing to cognitive decline in Alzheimer's disease. This Tau interaction with PSD-95 protein pockets reveals a novel molecular mechanism impacting synaptic function.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) is characterized by progressive memory loss and cognitive impairment.
- Postsynaptic localization of microtubule-associated protein Tau (Tau) is linked to cognitive deficits in AD.
- The precise role of Tau in postsynaptic dysfunction remains incompletely understood.
Purpose of the Study:
- To elucidate the molecular mechanism by which Tau influences postsynaptic protein dynamics.
- To investigate the interaction between Tau and key postsynaptic density (PSD) proteins.
- To explore potential therapeutic targets for modulating Tau-mediated synaptic dysfunction.
Main Methods:
- In vitro studies using purified proteins to assess Tau's effect on liquid-like protein droplets.
- Biophysical techniques to analyze Tau binding to PSD-95.
- Experiments with synthetic membranes to model NMDA receptor clusters.
- Investigating the impact of competitive peptide binding on protein dynamics.
Main Results:
- Tau was shown to arrest liquid-like droplets of PSD-95, GKAP, Shank, and Homer proteins.
- Tau binding to the GMP-binding pocket of PSD-95 was identified as crucial for this arrest.
- Tau-mediated arrest of NMDA-receptor-associated protein clusters on synthetic membranes was observed.
- Competitive binding of a phosphorylated peptide to PSD-95 rescued the dynamics of NMDA receptor constructs.
Conclusions:
- Tau modulates the dynamic properties of the postsynaptic density by arresting protein clusters.
- This Tau-mediated arrest mechanism offers a new perspective on synaptic dysfunction in Alzheimer's disease.
- Targeting the Tau-PSD-95 interaction may represent a therapeutic strategy for AD.
