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Chemical biology approach to study the role of PDZ domain-mediated interactions in synaptic plasticity

Objective

Complex dynamic protein-protein interactions are the base of protein-based networks in cells. Among them, the synaptic connection between two neurons is one of the most challenging. The postsynaptic density (PSD) at excitatory synapses in the brain is a prototypical example of protein-based network whose nanoscale structure and composition determines cellular function. Moreover, dynamic regulation of PSD composition and receptor movement into or out of the PSD is the base of current molecular theories of learning and memory. However, the nature of this regulation remains poorly understood partly due to the lack of tools that would allow disruption and control of specific interactions.
Several key components of the PSD such as PSD-95 contain multiple PDZ domains and the interactions mediated by these small domains are involved in critical events such as synaptic targeting and anchoring of glutamate receptors (AMPARs, NMDARs). The aim of this project is to design and exploit original tools to better understand the role of PDZ domain-mediated interactions in the context of synaptic plasticity by employing a chemical biology approach associating synthesis, biophysical measurements and live cell studies. In particular two different aspects will be addressed: 1) development of efficient and specific competing biomimetic ligands that integrate the multivalent nature of these interactions and 2) spatio-temporal control of the disruption of these PDZ domain-mediated interactions by incorporating to the previous ligands photolabile caging groups. The specific targets comprise on the one hand the main synaptic PDZ domain-containing scaffolding proteins (PSD-95, SAP97, PSD-93 and SAP102) and on the other AMPA and NMDA receptor complexes. Finally, these tools will complement common biological approaches by allowing us to study localized and dynamic macromolecular events between endogenous proteins.
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Coordinator

UNIVERSITE VICTOR SEGALEN BORDEAUX II

Address

Rue Leo Saignat 146
33076 Bordeaux Cedex

France

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 185 248

Administrative Contact

Daniel Choquet (Dr.)

Project information

Grant agreement ID: 273817

Status

Closed project

  • Start date

    1 May 2011

  • End date

    30 April 2013

Funded under:

FP7-PEOPLE

  • Overall budget:

    € 185 248

  • EU contribution

    € 185 248

Coordinated by:

UNIVERSITE VICTOR SEGALEN BORDEAUX II

France