The effect of S427F mutation on RXRα activity depends on its dimeric partner

<p>Simulations for RXRa-RARa can be found at:&nbsp;https://repo.vi-seem.eu/handle/21.15102/VISEEM-169&nbsp;</p> <p>Below are the datasets of the MD simulations&nbsp;RXR&alpha;-RXR&alpha; and RXR&alpha;-PPAR&gamma; for the paper:</p> <p>&quot;The effect of S427F mutation on RXR&alpha; activity depends on its dimeric partner&quot;, Galdadas et al, 2021, Chemical Science.</p> <p>RXRs are nuclear receptors acting as transcription regulators that control key cellular processes in all tissues. All type II nuclear receptors require RXRs for transcriptional activity by forming heterodimeric complexes. Recent whole-exome sequencing studies have identified the RXR&alpha; S427F hotspot mutation in 5% of the bladder cancer patients, which is always located at the interface of RXR&alpha; with its obligatory dimerization partners. Here, we show that mutation of S427 deregulates transcriptional activity of RXR&alpha; 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 RXR&alpha; 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.</p>