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Molecular & Cellular Proteomics 8:2212-2226, 2009.
© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Nuclear Receptor-Coregulator Interaction Profiling Identifies TRIP3 as a Novel Peroxisome Proliferator-activated Receptor Cofactor^*,

Arjen Koppen^,, Rene Houtman^¶, Dirk Pijnenburg^¶, Ellen H. Jeninga^,, Rob Ruijtenbeek^¶ and Eric Kalkhoven^,,||,**

From the Departments of Metabolic and Endocrine Diseases and
||Pediatric Immunology, University Medical Centre Utrecht, 3584 EA Utrecht, The Netherlands,
¶ PamGene International B.V., Nieuwstraat 30, 5211 NL 's-Hertogenbosch, The Netherlands, and
Netherlands Metabolomics Centre, Einsteinweg 55, 2333 CC Leiden, The Netherlands

Nuclear receptors (NRs) are major targets for drug discovery and have key roles in development and homeostasis as well as in many diseases such as obesity, diabetes, and cancer. NRs are ligand-dependent transcription factors that need to work in concert with so-called transcriptional coregulators, including corepressors and coactivators, to regulate transcription. Upon ligand binding, NRs undergo a conformational change, which alters their binding preference for coregulators. Short -helical sequences in the coregulator proteins, LXXLL (in coactivators) or LXXXIXXXL (in corepressors), are essential for the NR-coregulator interactions. However, little is known on how specificity is dictated. To obtain a comprehensive overview of NR-coregulator interactions, we used a microarray approach based on interactions between NRs and peptides derived from known coregulators. Using the peroxisome proliferator-activated receptor (PPAR) as a model NR, we were able to generate ligand-specific interaction profiles (agonist rosiglitazone versus antagonist GW9662 versus selective PPAR modulator telmisartan) and characterize NR mutants and isotypes (PPAR, -β/, and -). Importantly, based on the NR-coregulator interaction profile, we were able to identify TRIP3 as a novel regulator of PPAR-mediated adipocyte differentiation. These findings indicate that NR-coregulator interaction profiling may be a useful tool for drug development and biological discovery.

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