Molecular Basis of Signal Transduction

Our lab studies structures of the proteins and protein complexes involved in G-protein coupled receptor (GPCR) signaling pathways. GPCR signaling is responsible for the sensations of sight and smell, regulation of blood pressure and heart rate, and a host of intracellular events. When a trans-membrane GPCR is activated by an event outside of the cell, it undergoes a conformational change to activate heterotrimeric G proteins within the cell. Activated G proteins then initiate cascades that lead to profound physiological changes. Towards this end, we have solved several structures of G-proteins in both their active and inactive states, and in complex with their downstream effectors.

The current focus of our lab is to determine atomic structures of signaling proteins regulated by heterotrimeric G proteins; particularly those that contain RGS homology (RH) domains. One such target is GRK2, a kinase that is important for myocardiogenesis and regulation of heart contractility. GRK2 has been strongly implicated in the progression of congestive heart failure. We recently determined the atomic structure of GRK2 in complex with the heterotrimeric G proteins Gβγ. This was the first structure of an RH domain in the context of a modular enzyme, and the first of Gβγ in complex with a downstream effector enzyme.

A second protein we are studying is leukemia-associated RhoGEF (LARG). This protein binds to the heterotrimeric G proteins Gα12 and 13, partially via its RH domain. In response to Gα12/13 binding, LARG activates RhoA. RhoA is a small-molecular weight G protein which regulates cell shape and migration. Thus, LARG represents one of the few well-defined links between heterotrimeric G proteins and small-molecular weight G proteins. We are currently working on determining the atomic structures of various fragments and complexes of LARG that will allow us to understand the mechanism of signal transduction from Gα13 to RhoA.