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Helen Mott

Structure, function and dynamics of small G proteins and their downstream effectors

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. Once we understand how these proteins bind to each other, we  have the necessary tools to design molecules that inhibit or augment such interactions and we have used stapled peptides to this effect. We are also interested in understanding the dynamics of small G proteins, which can be studied by NMR, and how these are affected by binding to membranes and to other molecules.

Lab members: Lira Puebla, Joanna Watson, George Sophocleous, Sam Chamberlain

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Key publications:

1. J.C. Thomas, J.M. Cooper, N.S. Clayton, C. Wang, M.A. White, C. Abell, D. Owen, H.R. Mott (2016) Inhibition of Ral GTPases using a stapled peptide approach. J Biol Chem. 291 18310-25.

2. J.R. Watson, H.M. Fox, D. Nietlispach, J.L. Gallop, D. Owen D, H.R. Mott (2016) Investigation of the Interaction between Cdc42 and Its Effector TOCA1: HANDOVER OF Cdc42 TO THE ACTIN REGULATOR N-WASP IS FACILITATED BY DIFFERENTIAL BINDING AFFINITIES. J Biol Chem. 291 13875-90

3. H.R. Mott, D. Owen (2015) Structures of Ras superfamily effector complexes: What have we learnt in two decades? Crit Rev Biochem Mol Biol. 50 85-133

4. L. J. Campbell, M. Peppa, M.D. Crabtree, A. Shafiq, N.F. McGough, H.R. Mott, D. Owen (2015) Thermodynamic mapping of effector protein interfaces with RalA and RalB. Biochemistry. 54 1380-9.

5. K.V. Rajasekar, L.J.Campbell, D.Nietlispach, D.Owen & H.R. Mott (2013) The Structure of the RLIP76 RhoGAP-Ral Binding Domain Dyad: Fixed Position of the Domains Leads to Dual Engagement of Small G Proteins at the Membrane. Structure. 21 2131-2142.

6. C.L. Hutchinson, P.N. Lowe, S.H. McLaughlin, H.R. Mott, D. Owen (2013) Differential Binding of RhoA, RhoB, and RhoC to Protein Kinase C-Related Kinase (PRK) Isoforms PRK1, PRK2, and PRK3: PRKs Have the Highest Affinity for RhoB. Biochemistry. 52 7999-801.

7.  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.