Probing synaptic protein interactions in a vesicular model system
Lead Research Organisation:
Imperial College London
Department Name: Life Sciences
Abstract
The pre-synaptic terminal of a neural cell is one of the busiest and complex places in an organism. Its main purpose is to carry an action potential at a millisecond-time scale, which requires rapid and highly specific vesicular transport of neurotransmitters. This tremendous task is spearheaded by a vast array of pre-synaptic proteins, which are the key focus of this study. A number of pre-synaptic proteins are directly implicated in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Currently, we greatly lack in understating of the exact role synaptic proteins play and how they contribute to nervous system pathologies.
This study aims to develop an in vitro vesicular model system which would provide a platform for studying protein-protein interactions under more physiologically relevant protein conditions and conformations than only in a solution. Furthermore, the model system would be a universal platform for a number of structural and functional studies by solution and solid-state NMR, Förster resonance energy transfer (FRET) and fluorescence correlation spectroscopy (FCS). The techniques would greatly aid to characterise protein-protein interactions, define binding kinetics and reveal key-structural information on their interactions in a highly-controlled, systematic and reproducible way. In addition, several key-factors such as protein post-translational modifications, SUV compositions and metal ions involved in cellular signalling suggested to contribute presynaptic protein-protein interactions with other proteins can also be explored. Eventually, this platform could be applied to study the interactions of other pre-synaptic proteins. The study seeks to look at pre-synaptic proteins in a novel way and identify structural features of protein-protein interactions. It would also contribute to our greater understating of how intrinsically disordered proteins manifest their specificity towards other molecules and hopefully enrich our knowledge on neurodegenerative diseases such as Alzheimer's and Parkinson's.
This study aims to develop an in vitro vesicular model system which would provide a platform for studying protein-protein interactions under more physiologically relevant protein conditions and conformations than only in a solution. Furthermore, the model system would be a universal platform for a number of structural and functional studies by solution and solid-state NMR, Förster resonance energy transfer (FRET) and fluorescence correlation spectroscopy (FCS). The techniques would greatly aid to characterise protein-protein interactions, define binding kinetics and reveal key-structural information on their interactions in a highly-controlled, systematic and reproducible way. In addition, several key-factors such as protein post-translational modifications, SUV compositions and metal ions involved in cellular signalling suggested to contribute presynaptic protein-protein interactions with other proteins can also be explored. Eventually, this platform could be applied to study the interactions of other pre-synaptic proteins. The study seeks to look at pre-synaptic proteins in a novel way and identify structural features of protein-protein interactions. It would also contribute to our greater understating of how intrinsically disordered proteins manifest their specificity towards other molecules and hopefully enrich our knowledge on neurodegenerative diseases such as Alzheimer's and Parkinson's.
Organisations
Publications
Fusco G
(2018)
Order and disorder in the physiological membrane binding of a-synuclein.
in Current opinion in structural biology
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M011178/1 | 01/10/2015 | 25/02/2025 | |||
| 1656811 | Studentship | BB/M011178/1 | 03/10/2015 | 30/09/2019 |
| Description | I have optimised and performed NMR experiments on pre-synaptic proteins in an in vitro model system. I have discovered some novel, unexpected properties of proteins which govern vesicular tethering. The finding may lead to reviewing the current molecular models developed to explain synaptic vesicular transport. |
| Exploitation Route | The methodologies which I developed in theory could be applied to a number of other pre-synaptic proteins and their studies in vitro model systems. These might help aid the understanding of molecular mechanisms in neurological disorders and develop novel therapeutics to combat them. |
| Sectors | Education,Pharmaceuticals and Medical Biotechnology |