Research group leaders
Small GTPases (G proteins) of the Ras superfamily are intimately involved in a number of cellular processes, including cell cycle progression, inhibition of apoptosis, cytoskeletal rearrangements, adhesion, nuclear transport and vesicle trafficking. Their deregulation has been linked with diseases such as cancer. Small GTPases signal through a number of downstream effector proteins, which are enzymes (eg kinases), adaptor proteins or multidomain, multi-functional proteins.
The structures of several 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. One objective of our 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 the complexes formed by GTPases and their effectors. These structures can be used to determine which residues contribute thermodynamically to the interface. If we can understand how these proteins bind to each other, we will have the necessary tools to design molecules that inhibit or augment such interactions. We are also investigating how the functions of the effector proteins themselves are modulated by their binding to small GTPases.
Lab members: Lira Puebla, Arooj Shafiq
1. R. B. Fenwick, L.J. Campbell, K. Rajasekar, S. Prasannan, D. Nietlispach, J. Camonis, D. Owen & H.R. Mott (2010) The RalB-RLIP76 complex reveals a novel mode of ral-effector interaction. Structure 18 985-995.
2. L.K. Bailey, L.J. Campbell, K.A. Evetts, K. Littlefield, E. Rajendra, D. Nietlispach, D. Owen & H.R. Mott. (2009) "The structure of binder of Arl2 (BART) reveals a novel G protein binding domain: Implications for function." J. Biol. Chem. 284 992-999.
3. R. Modha, L.J. Campbell, D. Nietlispach, H.R. Buhecha, D. Owen & H.R. Mott (2008) "The Rac1 polybasic region is required for interaction with its effector PRK1." J. Biol. Chem. 283 1492-500.