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Applications of mini G proteins to study G protein-coupled receptors
Published on January 30, 2020 25 min
Other Talks in the Series: G Protein-Coupled Receptors (GPCRs) signaling in health and disease
Computational modelling of GPCR signalling dynamics
- Dr. Graham Ladds
- University of Cambridge, UK
Super-resolution imaging of GPCR oligomers: applications and functional roles
- Dr. Aylin Hanyaloglu
- Imperial College London, UK
Structure and activation of endothelin ETB receptor by endothelin
- Dr. Tomoko Doi
- Kyoto University, Japan
Structural and mechanistic insights into the neurotensin receptor
- Dr. Reinhard Grisshammer
- National Cancer Institute, USA
Adhesion GPCRs in nervous system development and disease
- Prof. Tobias Langenhan
- Leipzig University, Germany
Hello. My name is Byron Carpenter and I'm a Research Fellow at the University of Warwick. This lecture will cover the development of mini-G proteins and their applications to study the structure and function of G protein-coupled receptors.
I'll begin this presentation with an introduction to G protein-coupled receptors, which would be referred to as GPCRs from now on. Next, I'll give an overview of the development of mini G proteins, I'll then cover the applications in GPCR structural biology. As a case study, I'll look at the crystallization of the adenosine A2A receptor in complex with mini-G protein. I'll then talk about their applications in GPCR functional studies, and finally I'll end with a summary of our findings.
GPCRs are cell surface receptors that regulate many aspects of eukaryotic cell behavior. Their role is to recognize extracellular signaling molecules and transmit this information across the cell membrane to activate intracellular signaling cascades. There are over 400 nonolfactory GPCRs in the human genome and they recognize a wide variety of different signaling molecules, including small molecule hormones such as adrenaline, peptides such as neurotensin, and multi-chain glycoproteins such as the follicle stimulating hormone as shown at the top of the slide. When an agonist binds to a receptor, it initiates a subtle conformational and energetic changes that are propagated to its cytoplasmic surface as shown on the left-hand side of the slide. In this conformation, the receptor can efficiently interact with heterotrimeric G proteins, which are the predominant class of signaling protein activated by GPCRs. The G protein cell is composed of an alpha sub-unit and a beta-gamma dimer. In its basal state, it's bound to a molecule of GTP. When the stimulated receptor interacts with the G protein, it catalyzes the dissociation of GTP from the alpha sub-unit. GTP then binds due to its high cellular concentration. This activates the G protein, which causes it to dissociate from the receptor and triggers the alpha and beta gamma sub-units to dissociate from one another. These components are then in their active state and are able to stimulate their respective downstream signaling cascades. In the case of G alpha (s) , it activates adenylate cyclase, which increases cyclic AMP concentrations within the cell. The beta-gamma dimer regulates other signaling proteins including kinases and ion channels.