The effect of S427F mutation on RXRα activity depends on its dimeric partner
| Autor: | Zoe Cournia, Ioannis Galdadas, Paraskevi Vgenopoulou, Georgia Stergiou, Michail Papadourakis, Vangelis Bonis, Panos Kakoulidis, Apostolos Klinakis |
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| Rok vydání: | 2021 |
| Předmět: |
0303 health sciences
Mutation Transcriptional activity Chemistry Allosteric regulation General Chemistry Retinoid X receptor medicine.disease_cause 3. Good health Cell biology 03 medical and health sciences 0302 clinical medicine Nuclear receptor Transcription (biology) Mutant protein medicine 030217 neurology & neurosurgery Function (biology) 030304 developmental biology |
| Zdroj: | Chemical Science |
| ISSN: | 2041-6539 2041-6520 |
| Popis: | 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 RXRα S427F hotspot mutation in 5% of the bladder cancer patients, which is always located at the interface of RXRα with its obligatory dimerization partners. Here, we show that mutation of S427 deregulates transcriptional activity of RXRα 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 RXRα 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. A cancer-associated missense mutation in the nuclear receptor RXRα acts by allosteric mechanisms and impacts differently the activity of its dimers, depending on the dimerization partner. |
| Databáze: | OpenAIRE |
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