Definition of the surface in the thyroid hormone receptor ligand binding domain for association as homodimers and heterodimers with retinoid X receptor

Citation
Rcj. Ribeiro et al., Definition of the surface in the thyroid hormone receptor ligand binding domain for association as homodimers and heterodimers with retinoid X receptor, J BIOL CHEM, 276(18), 2001, pp. 14987-14995
Citations number
47
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
276
Issue
18
Year of publication
2001
Pages
14987 - 14995
Database
ISI
SICI code
0021-9258(20010504)276:18<14987:DOTSIT>2.0.ZU;2-K
Abstract
Thyroid hormone receptors (TRs) bind as homodimers or heterodimers with ret inoid X receptors (RXRs) to DNA elements with diverse orientations of AGGTC A half-sites. We performed a comprehensive x-ray crystal structure-guided m utation analysis of the TR ligand binding domain (TR LED) surface to map th e functional interface for TR homodimers and heterodimers with RXR in the a bsence and/or in the presence of DNA. We also identified the molecular cont acts in TR LBDs crystallized as dimers. The results show that crystal dimer contacts differ from those found in the functional studies. We found that identical TR LED residues found in helices 10 and 11 are involved in TR hom odimerization and heterodimerization with RXR. Moreover, the same TR LED su rface is operative for dimerization with direct repeats spaced by 4 base pa irs (DR-4) and with the inverted palindrome spaced by 6 base pairs (F2), bu t not with TREpal (unspaced palindrome), where homodimers appear to be simp ly two monomers binding independently to DNA. We also demonstrate that inte ractions between the TR and RXR DNA binding domains stabilize TR-RXR hetero dimers on DR-4. The dimer interface can be functional in the cell, because disruption of key residues impairs transcriptional activity of TRs mediated through association with RXR LED linked to GAL4 DNA-binding domain.