Helen Mott

Structure, dynamics and membrane interactions 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 (e.g. 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 the research in the Mott Group 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 in molecular detail by NMR, and how these are affected by binding to membranes and to other proteins. Finally, we are investigating interactions between small G proteins and membranes, and how this modulates binding of effectors and regulators.​

Research objectives

• Can we inhibit small G proteins with stabilised alpha-helical peptides?

• How does the dynamics of small G proteins change in cancer-associated mutants?

• How do small G proteins interact with the membrane to which they are tethered?

• What role does the membrane have in assembling signalling complexes involving small G proteins?

Key publications

Watson JR, Fox HM, Nietlispach D, Gallop JL, Owen D, Mott HR (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(26):13875-13890. doi: 10.1074/jbc.M116.724294

Mott HR, Owen D (2018). Allostery and dynamics in small G proteins. Biochem. Soc. Trans., 46(5):1333-1343. doi: 10.1042/BST20170569

Thomas JC, Cooper JM, Clayton NS, Wang C, White MA, Abell C, Owen D, Mott HR (2016). Inhibition of Ral GTPases using a stapled peptide approach. J. Biol. Chem., 291(35):18310-18325. doi: 10.1074/jbc.M116.720243

Mott HR, Owen D (2015). Structures of Ras superfamily effector complexes: What have we learnt in two decades? Crit. Rev. Biochem. Mol. Biol., 50(2):85-133. doi: 10.3109/10409238.2014.999191

Tetley GJN, Szeto A, Fountain AJ, Mott HR, Owen D (2018). Bond swapping from a charge cloud allows flexible coordination of upstream signals through WASP: Multiple regulatory roles for the WASP basic region. J. Biol. Chem., 293(39):15136-15151. doi: 10.1074/jbc.RA118.003290