Biomedical Research Foundation Academy Of AthensAcademy Of Athens
Research Highlights :The effect of S427F mutation on RXRα activity depends on its dimeric partner


Apostolos Klinakis, Zoe Cournia and colleagues recently published a study in Chemical Science

RXRs are nuclear receptors that control key cellular processes in all tissues. Recent sequencing studies have identified the RXRa S427F hotspot mutation in 5% of the bladder cancer patients, which is always located at the interface of RXRa with its protein dimerization partners. Here, we show that mutation of S427 deregulates transcriptional activity of RXRa dimers, albeit with diverse allosteric mechanisms of action depending on its dimeric partner. S427F acts by allosteric mechanisms, which range from inducing the collapse of the binding pocket to allosteric stabilization of active co-activator competent RXRa states. Unexpectedly, RXR S427F heterodimerization leads to either loss- or gain-of-function complexes, in both cases likely compromising its tumor suppressor activity. This is the first report of a cancer-associated single amino acid substitution that affects the function of the mutant protein variably depending on its dimerization partner.

The effect of S427F mutation on RXRα activity depends on its dimeric partner
Galdadas I, Bonis V, Vgenopoulou P, Papadourakis M, Kakoulidis P, Stergiou G, Cournia Z*, Klinakis A.*
Chem Sci. 2021 Oct 8;12(44):14700-14710. doi: 10.1039/d1sc04465f. eCollection 2021 Nov 17.