Small GTPases, in association with their GEFs, GAPs and effectors, control major intracellular processes such as signal transduction, cytoskeletal dynamics and membrane trafficking. Accordingly, dysfunctions in their biochemical properties are associated with many diseases, including cancers, diabetes, infections, mental disorders and cardiac diseases, which makes them attractive targets for therapies. However, small GTPases signalling modules are not well-suited for classical inhibition strategies due to their mode of action that combines protein–protein and protein–membrane interactions. As a consequence, there is still no validated drug available on the market that target small GTPases, whether directly or through their regulators. Alternative inhibitory strategies are thus highly needed. Here we review recent studies that highlight the unique modalities of the interaction of small GTPases and their GEFs at the periphery of membranes, and discuss how they can be harnessed in drug discovery.
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Cover Image
Cover Image
The plasma membrane of lymphocytes is highly compartmentalized in so-called nanodomains or protein islands. Proteins such as Caveolin-1 (pink), tetraspanins (blue) or flotillins (violet) define these protein islands and thereby regulate the functioning of the immune system. In this issue (see pages 2387–2397), Schaffer and Minguet discuss the importance of these protein islands regarding lymphocyte activation and the development of immunopathologies. This cover artwork has been created by Susana Minguet.
Protein–membrane interactions in small GTPase signalling and pharmacology: perspectives from Arf GTPases studies
Agata Nawrotek, Mahel Zeghouf, Jacqueline Cherfils; Protein–membrane interactions in small GTPase signalling and pharmacology: perspectives from Arf GTPases studies. Biochem Soc Trans 18 December 2020; 48 (6): 2721–2728. doi: https://doi.org/10.1042/BST20200482
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