Millisecond to Microsecond Time Scale Dynamics of the Retinoid X and Retinoic Acid Receptor DNA-Binding Domains and Dimeric Complex Formation

• Published in: Biochemistry (Easton) Vol. 38; no. 7; pp. 1951 - 1956
• Main Authors: van Tilborg, Paul J. A, Mulder, Frans A. A, de Backer, Maaike M. E, Nair, Margie, van Heerde, Erika C, Folkers, Gert, van der Saag, Paul T, Karimi-Nejad, Yasmin, Boelens, Rolf, Kaptein, Robert
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 16.02.1999
• Subjects: Amino Acid Sequence; Dimerization; DNA - metabolism; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; Humans; Macromolecular Substances; Models, Molecular; Molecular Sequence Data; Nuclear Magnetic Resonance, Biomolecular; Protein Structure, Tertiary; Receptors, Retinoic Acid - chemistry; Receptors, Retinoic Acid - metabolism; Retinoid X Receptors; Thermodynamics; Time Factors; Transcription Factors - chemistry; Transcription Factors - metabolism
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/bi982526q

The all-trans retinoic acid and 9-cis retinoic acid receptors (RAR and RXR, respectively) belong to a family of ligand inducible transcription factors, which exert their effect via binding to hormone response elements. Both are members of the class II sub-family of nuclear receptors, which bind DNA as dimers, on tandem repeats of a hexamer motif separated by a variable spacer. The variability in spacer length and the head-to-tail organization of the hormone response elements result in different protein−protein interactions in each of the complexes. We show that the zinc-coordinating loop regions of RXR and RAR DNA-binding domains exhibit dynamics on the millisecond to microsecond time scale. The highly dynamic second zinc finger of RXR constitutes the primary protein−protein interface in many nuclear receptor assemblies on DNA. Dynamics is also observed in the first and second zinc fingers of RAR, which are implicated in dimeric interactions with RXR on response elements with spacers of 5 base pairs and 1 base pair, respectively. The striking correspondence between the regions that exhibit conformational exchange and the dimer interfaces of the proteins complexed with DNA suggests a functional role for the dynamics. The observed flexibility may allow the proteins to adapt to various partners and with different orientations upon assembly on DNA. Furthermore, the more extensive dynamics observed for RXR may reflect the greater ability of this protein to modulate its interaction surface since it participates in a wide variety of receptor complexes.