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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Structural rearrangements in the thyroid hormone receptor hinge domain and their putative role in the receptor function

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Nascimento, Alessandro S. ; Dias, Sandra Martha Gomes ; Nunes, Fábio M. ; Aparício, Ricardo ; Ambrosio, Andre L. B. ; Bleicher, Lucas ; Figueira, Ana Carolina M. ; Santos, Maria Auxiliadora M. ; Oliveira Neto, Mário de ; Fischer, Hannes ; et al
Total Authors: 11
Document type: Journal article
Source: Journal of Molecular Biology; v. 360, n. 3, p. 586-598, July 2006.
Field of knowledge: Biological Sciences - Biophysics

The thyroid hormone receptor (TR) D-domain links the ligand-binding domain (LBD, EF-domain) to the DNA-binding domain (DBD, C-domain), but its structure, and even its existence as a functional unit, are controversial. The D domain is poorly conserved throughout the nuclear receptor family and was originally proposed to comprise an unfolded hinge that facilitates rotation between the LBD and the DBD. Previous TR LBD structures, however, have indicated that the true unstructured region is three to six amino acid residues long and that the D-domain N terminus folds into a short amphipathic ALPHA-helix (H0) contiguous with the DBD and that the C terminus of the D-domain comprises H1 and H2 of the LBD. Here, we solve structures of TR-LBDs in different crystal forms and show that the N terminus of the TR-ALPHA D-domain can adopt two structures; it can either fold into an amphipathic helix that resembles TR-BETA H0 or form an unstructured loop. H0 formation requires contacts with the AF-2 coactivator-binding groove of the neighboring TR LBD, which binds H0 sequences that resemble coactivator LXXLL motifs. Structural analysis of a liganded TR LBD with small angle X-ray scattering (SAXS) suggests that AF-2/H0 interactions mediate dimerization of this protein in solution. We propose that the TR D-domain has the potential to form functionally important extensions of the DBD and LBD or unfold to permit TRs to adapt to different DNA response elements. We also show that mutations of the D domain LXXLL-like motif indeed selectively inhibit TR interactions with an inverted palindromic response element (F2) in vitro and TR activity at this response element in cell-based transfection experiments. (AU)

FAPESP's process: 06/00182-8 - Structural biophysics of nuclear receptors and related proteins
Grantee:Igor Polikarpov
Support type: Research Projects - Thematic Grants