NMR spectroscopic studies of the DNA-binding domain of the monomer- binding nuclear orphan receptor, human estrogen related receptor-2: The carboxyl-terminal extension to the zinc-finger region is unstructured in the free form of the protein

Daniel S. Sem, Danilo R. Casimiro, Steven A. Kliewer, Joan Provencal, Ronald M. Evans, Peter E. Wright

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Unlike steroid and retinoid receptors, which associate with DNA as dimers, human estrogen related receptor-2 (hERR2) belongs to a growing subclass of nuclear hormone receptors that bind DNA with high affinity as monomers. A carboxyl-terminal extension (CTE) to the zinc-finger domain has been implicated to be responsible for determining the stoichiometry of binding by a nuclear receptor to its response element. To better understand the mechanism by which DNA specificity is achieved, the solution structure of the DNA-binding domain of hERR2 (residues 96-194) consisting of the two putative zinc fingers and the requisite 26-amino acid CTE was analyzed by multidimensional heteronuclear magnetic resonance spectroscopy. The highly conserved zinc-finger region (residues 103-168) has a fold similar to those reported for steroid and retinoid receptors, with two helices that originate from the carboxyl-terminal ends of the two zinc fingers and that pack together orthogonally, forming a hydrophobic core. The CTE element of hERR2 is unstructured and highly flexible, exhibiting nearly random coil chemical shifts, extreme sensitivity of the backbone amide protons to solvent presaturation, and reduced heteronuclear (1H-15N) nuclear Overhauser effect values. This is in contrast to the dimer-binding retinoid X and thyroid hormone receptors, where, in each case, a helix has been observed within the CTE. The implications of this property of the hERR2 CTE are discussed.

Original languageEnglish (US)
Pages (from-to)18038-18043
Number of pages6
JournalJournal of Biological Chemistry
Volume272
Issue number29
DOIs
StatePublished - Jul 18 1997

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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