Separation of Retinoid X Receptor Homo- and Heterodimerization Functions
| Autor: | Valerie Vivat-Hannah, Marco M. Gottardis, William Bourguet, Hinrich Gronemeyer |
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| Jazyk: | angličtina |
| Rok vydání: | 2003 |
| Předmět: |
Models
Molecular Protein Conformation Receptors Retinoic Acid Mutant Molecular Sequence Data Biology Retinoid X receptor medicine.disease_cause Mice Two-Hybrid System Techniques medicine Animals Amino Acid Sequence Molecular Biology Transcription factor Transcriptional Regulation Mutation COS cells organic chemicals Retinoic Acid Receptor alpha Cell Biology Cell biology body regions Retinoic acid receptor Retinoid X Receptors Biochemistry Nuclear receptor embryonic structures COS Cells Mutagenesis Site-Directed lipids (amino acids peptides and proteins) Signal transduction Dimerization Sequence Alignment hormones hormone substitutes and hormone antagonists Signal Transduction Transcription Factors |
| Popis: | As a promiscuous dimerization partner the retinoid X receptor (RXR) can contribute to signaling by multiple nuclear receptors. However, the impact of RXR cosignaling and the possible existence of an RXR homodimer signaling pathway are largely unexplored. We report here on the separation of RXR homo- and heterodimerization as an essential step towards the elucidation of the roles of RXR homo- and heterodimers in retinoid-rexinoid signaling. RXR homodimerization was specifically disrupted by single mutations in the RXR dimerization interface. In contrast, even multiple mutations did not fully impair RXR heterodimerization with retinoic acid receptor (RAR). Importantly, the mutation of mouse RXRalpha (mRXRalpha) Tyr402 substantially weakened RAR heterodimerization while concomitantly increasing homodimerization. Not only did this lead to cooperatively enhanced RXR homodimer binding to DR1 or DR5 elements, but unexpectedly, the mutant acquired significant binding efficiency for noncognate DR3 or DR4 elements as well. The increased stability of RXR homodimers on DR1 correlated with increased transcriptional activity of mRXRalpha(Y402A) on DR1-based reporter genes. Weak, if any, heterodimerization was observed with thyroid, vitamin D(3), or peroxisome proliferator-activating receptors. A model accounting for the structural impact of the Tyr402 mutation on dimerization is discussed. These results provide the basis for a genetic replacement of wild-type RXRs by mutants like mRXRalpha(Y402A) to elucidate the physiological impact of RXR homo- and heterodimerization. |
| Databáze: | OpenAIRE |
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