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Protein-Protein Interactions in Small G Protein/Effector Complexes

Research Groupings: Structural and molecular cell biology | Cancer

Small GTPases (or G proteins) of the Ras superfamily are intimately involved in a number of cellular processes, such as cell cycle progression, inhibition of apoptosis, cytoskeletal rearrangements, adhesion, nuclear transport and vesicle trafficking. They signal through a number of downstream effector proteins, which activate a single pathway or contribute to several pathways.

Structures of the Cdc42/ACK and Cdc42/PAK complexes solved by our laboratory using multi-dimensional NMR

The structures of some small G protein/effector complexes have been elucidated and it is clear that great diversity exists in the various effectors and how they contact GTPases. The primary objective of this research is to understand how small GTPases can recognise a large number of effector molecules with such exquisite specificity. The first step in such an investigation is the determination of the structures of several complexes. These structures can be used to design mutants, to determine which residues contribute thermodynamically to the interface. Knowledge of protein-protein interactions is fundamental to our understanding of how cells function in the context of a multi-cellular organism. If we can understand how proteins interact, we will have the necessary tools to design molecules that inhibit or augment such interactions.

As well as solving structures, we can use chemical shift mapping (left) to determine the binding contacts on one protein for another (right). In this case, we show the binding site of Ral on the exocyst component Sec5.

At present, we are concentrating our efforts on small GTPases of the Rho family that control actin cytoskeleton and cell adhesion; the Ras and Rho family that control polarised exocytosis and the Arl family that control vesicle transport. We are using a combination of multi-dimensional NMR spectroscopy and biochemical techniques to study the details of these interactions. This work is undertaken in collaboration with the Biomolecular NMR Facility in the Department of Biochemistry.

Lab members
Laura Bailey, R Bryn Fenwick, Karthik Rajasekar

References