The Structural Biology of Memory
Lead Research Organisation:
University of Oxford
Department Name: Structural Biology
Abstract
We are interested in understanding the molecular mechanisms responsible for acquisition and storage of information in the brain, i.e. learning and memory. Research over the past five decades led to the idea that activity-dependent changes in the strength of synapses between nerve cells (synaptic plasticity) can represent a mechanism for information storage. The neurotransmitters glutamate and ?-amino-butyric acid (GABA) mediate most synaptic signalling in the vertebrate central nervous system. Their receptors play important roles in the induction, expression and/or modulation of synaptic plasticity. Dysfunction of these molecular systems appears to be responsible for the cognitive decline linked to the ‘normal‘ aging process. From a medical point of view, a wide spectrum of disorders including Alzheimer‘s, Parkinson‘s, schizophrenia, bipolar disorder, major clinical depression as well as ischemic neuronal injury are linked to the same receptor molecules.
Our research is currently focused on the structural characterization of glutamate and GABA receptors, our main tool being X-ray crystallography. We aim to understand the molecular mechanisms governing their assembly, function and regulation, and to devise ways of modulating their signalling properties. This work is performed using cells grown in culture and state-of-the-art technology including robots for growing protein crystals and synchrotron-generated X-rays.
Our research is currently focused on the structural characterization of glutamate and GABA receptors, our main tool being X-ray crystallography. We aim to understand the molecular mechanisms governing their assembly, function and regulation, and to devise ways of modulating their signalling properties. This work is performed using cells grown in culture and state-of-the-art technology including robots for growing protein crystals and synchrotron-generated X-rays.
Technical Summary
Synaptic plasticity provides the basis for information storage in the brain. This project combines structural (X-ray crystallography) and functional (biochemical, cellular, genetic and electrophysiological) approaches to characterize cell surface receptors important for synaptic transmission and plasticity and, by extension, for learning and memory. Specifically, the key goals are:
(i) to provide atomic level structural information on the glutamate, gamma-amino butyric acid (GABA) and Eph receptors;
(ii) to understand the binding mechanisms and molecular consequences of the interactions within the ephrin/Eph/NMDA receptor complexes;
(iii) to understand the functional significance of various structural elements from the above molecules and their role in signal transduction, in a cellular context.
This project relies on significant technological developments in structural biology, including large-scale expression of constructs derived from cell surface receptors in mammalian cells, nanoliter-scale crystallization and automated plate imaging systems as well as access to the latest generation synchrotron radiation facilities and electron microscopes. In addition, close collaborations with two leading laboratories actively involved in the characterisation of the receptors of interest (Seth Grant at the Wellcome Trust Sanger Institute and Jeff McIlhinney from the MRC Anatomical Neuropharmacology Unit in Oxford) will add an essential functional dimension to complement the structural work and contribute to a comprehensive understanding of these molecular systems.
The glutamate, GABA and Eph receptors have been extensively studied and the body of evidence coming from pharmacology, developmental biology, genetic and behavioural analysis overwhelmingly supports their functional importance. Recent structural results have also contributed significantly to the elucidation of the ligand binding mechanisms (in the case of glutamate receptors) and protein-protein interactions (in the Eph/ephrin signalling system). The major challenge now is to understand the allosteric mechanisms by which individual domains communicate and transduce signals across the plasma membrane, and this is the scientific niche where I hope this project will make a significant contribution.
From the medical point of view, a wide spectrum of disorders including Alzheimer‘s, schizophrenia, Parkinson‘s and ischemic neuronal injury are linked to cell surface receptors responsible for synaptic plasticity. Dysfunction of the same molecular systems appears to be responsible for the cognitive decline linked to the normal aging process or psychiatric conditions such as bipolar disorder and major clinical depression. Understanding the structure and mechanisms of action of the molecules involved can lead to better therapies and an improved quality of life.
(i) to provide atomic level structural information on the glutamate, gamma-amino butyric acid (GABA) and Eph receptors;
(ii) to understand the binding mechanisms and molecular consequences of the interactions within the ephrin/Eph/NMDA receptor complexes;
(iii) to understand the functional significance of various structural elements from the above molecules and their role in signal transduction, in a cellular context.
This project relies on significant technological developments in structural biology, including large-scale expression of constructs derived from cell surface receptors in mammalian cells, nanoliter-scale crystallization and automated plate imaging systems as well as access to the latest generation synchrotron radiation facilities and electron microscopes. In addition, close collaborations with two leading laboratories actively involved in the characterisation of the receptors of interest (Seth Grant at the Wellcome Trust Sanger Institute and Jeff McIlhinney from the MRC Anatomical Neuropharmacology Unit in Oxford) will add an essential functional dimension to complement the structural work and contribute to a comprehensive understanding of these molecular systems.
The glutamate, GABA and Eph receptors have been extensively studied and the body of evidence coming from pharmacology, developmental biology, genetic and behavioural analysis overwhelmingly supports their functional importance. Recent structural results have also contributed significantly to the elucidation of the ligand binding mechanisms (in the case of glutamate receptors) and protein-protein interactions (in the Eph/ephrin signalling system). The major challenge now is to understand the allosteric mechanisms by which individual domains communicate and transduce signals across the plasma membrane, and this is the scientific niche where I hope this project will make a significant contribution.
From the medical point of view, a wide spectrum of disorders including Alzheimer‘s, schizophrenia, Parkinson‘s and ischemic neuronal injury are linked to cell surface receptors responsible for synaptic plasticity. Dysfunction of the same molecular systems appears to be responsible for the cognitive decline linked to the normal aging process or psychiatric conditions such as bipolar disorder and major clinical depression. Understanding the structure and mechanisms of action of the molecules involved can lead to better therapies and an improved quality of life.
