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Séminaire - Reza Vafabakhsh / Conférence ANNULEVisualizing the information processing on the plasma membrane

Abstract :

The ability to sense external and internal signals and dynamically respond lies at the core of cellular homeostasis and membrane receptor complexes that receive and initiate transduction of the extracellular signals are at the heart of the cellular information processing. Therefore, a comprehensive mechanistic understanding of how membrane receptors sense and interpret signals is a fundamental problem in biology with practical implications for understanding disease mechanisms and engineering synthetic signaling and genetic circuits. In human, G protein-coupled receptor (GPCR) signaling is responsible for more than 80% of signal transduction across cell membranes and GPCRs are master regulators of key biological functions such as vision, metabolism, and neurotransmission.
Due to their central role in controlling nearly all aspects of human physiology and behavior, GPCRs have become the largest family of drug targets in modern medicine. My lab is working on Class C GPCRs which are composed of mGluRs, GABABRs, CaSR and sweet and umami taste receptors. Because of their central function in modulating the neuronal excitability, these receptors are powerful regulators of neuronal circuits and are widely considered to be critical drug targets for neurological and mental health disorders such as anxiety, schizophrenia, Parkinson’s disease, depression, drug dependency and autism spectrum disorders.
However, lack of the knowledge of the structural bases for the activation, dynamics and modulation of group C GPCRs has been an obstacle to their therapeutic targeting. In this talk I will describe our methodologies to measure the conformational dynamics of the group C GPCR complexes to understand how these receptors integrate the spatial and temporal information of the signal with the information from cellular microenvironment to generate their physiological response

 

Selected publications

Structural dynamics of potassium-channel gating revealed by single-molecule FRET. Wang S, Vafabakhsh R, Borschel WF, Ha T, and Nichols CG. Nature Structural & Molecular Biology. 2016 January;23(1):31-36.

Conformational dynamics of a class C G-protein-coupled receptor. Vafabakhsh R, Levitz J, and Isacoff EY. Nature. 2015 August 27;524(7566):497-501.

Single-molecule packaging initiation in real time by a viral DNA packaging machine from bacteriophage T4. Vafabakhsh R, Kondabagil K, Earnest T, Lee KS, Zhang Z, Dai L, Dahmen KA, Rao VB, and Ha T. PNAS.2014 October 21;111(42):15096-15101.

Extreme Bendability of DNA Less than 100 Base Pairs Long Revealed by Single-Molecule Cyclization. Vafabakhsh R and Ha T. Science. 2012 August 31;337(6098):1097-1101.

One influenza virus particle packages eight unique viral RNAs as shown by FISH analysis. Chou Y-Y, Vafabakhsh R, Doganay S, Gao Q, Ha T, and Palese P. PNAS. 2012 June 5;109(23):9101-9106.

Scientific focus :

The brain comprises of billions of neurons that are interconnected by synapses to communicate information. A single neuron is a powerful nonlinear computing device that receives a wide range of electrical and chemical inputs, process and integrate them locally and produce an output. A major challenge is to understand how synaptic biomolecules organize into dynamic computational cassettes that converse together to create complexity and adapt the flow of local “information” to specific inter-neuronal activities. The higher order functionalities of the brain are an emergent property of such dynamics.

We study the flow of information, from a single protein level to the neuron level, to try to understand the molecular nature of information processing in the brain. Such knowledge is fundamental for understanding normal brain functions and neurological disorders. We are doing so by using highly interdisciplinary analyses along with cutting edge single molecule and high throughput approaches that draw from physics, chemistry, cell biology and engineering.