| First Author | Chen L | Year | 2017 |
| Journal | Nat Commun | Volume | 8 |
| Pages | 16066 | PubMed ID | 28714476 |
| Mgi Jnum | J:249683 | Mgi Id | MGI:5920670 |
| Doi | 10.1038/ncomms16066 | Citation | Chen L, et al. (2017) Modulation of nongenomic activation of PI3K signalling by tetramerization of N-terminally-cleaved RXRalpha. Nat Commun 8:16066 |
| abstractText | Retinoid X receptor-alpha (RXRalpha) binds to DNA either as homodimers or heterodimers, but it also forms homotetramers whose function is poorly defined. We previously discovered that an N-terminally-cleaved form of RXRalpha (tRXRalpha), produced in tumour cells, activates phosphoinositide 3-kinase (PI3K) signalling by binding to the p85alpha subunit of PI3K and that K-80003, an anti-cancer agent, inhibits this process. Here, we report through crystallographic and biochemical studies that K-80003 binds to and stabilizes tRXRalpha tetramers via a 'three-pronged' combination of canonical and non-canonical mechanisms. K-80003 binding has no effect on tetramerization of RXRalpha, owing to the head-tail interaction that is absent in tRXRalpha. We also identify an LxxLL motif in p85alpha, which binds to the coactivator-binding groove on tRXRalpha and dissociates from tRXRalpha upon tRXRalpha tetramerization. These results identify conformational selection as the mechanism for inhibiting the nongenomic action of tRXRalpha and provide molecular insights into the development of RXRalpha cancer therapeutics. |
