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Molecular determinants required for selective interactions between the thyroid hormone receptor homodimer and the

Ji Young Kim1, You Lee Son, Jeong-Sun Kim

  • 1Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.

Journal of Molecular Biology
|December 17, 2009
PubMed

Insights

Thyroid hormone receptor (TR) preferentially binds nuclear receptor corepressor (N-CoR) via its ID3 domain. Specific C-terminal residues in N-CoR-ID3 mediate this TR interaction, revealing a novel binding mechanism for nuclear receptors.

Area of Science:

  • Molecular biology
  • Endocrinology
  • Structural biology

Background:

  • Nuclear receptors (NRs) recruit corepressors like N-CoR via interaction domains (IDs).
  • Thyroid hormone receptor (TR) specifically interacts with N-CoR's ID3 domain, distinct from typical helical motifs.
  • The molecular basis for TR's preference for N-CoR-ID3 remains unclear.

Purpose of the Study:

  • To investigate the molecular determinants governing the interaction between TR and N-CoR-ID3.
  • To elucidate the structural basis for TR's selective binding to N-CoR-ID3.

Main Methods:

  • Utilized one-plus-two-hybrid systems to identify key residues.
  • Performed swapping experiments and mutagenesis studies.
  • Employed structural modeling of the ID3 motif on the TR ligand-binding domain (LBD).

Main Results:

  • Identified specific residues in N-CoR-ID2 and N-CoR-ID3 crucial for stable N-CoR-TR homodimer association.
  • Determined that C-terminally flanking residues of the N-CoR-ID3 core motif confer TR preference.
  • Structural modeling supports the formation of an extended helix in ID3 for TR-specific interaction.
  • Discovered a novel interaction between N-CoR-ID3 and orphan NR RevErb, mediated by TR-binding residues.

Conclusions:

  • TR homodimers exhibit preferential binding to N-CoR-ID3 through specific interactions mediated by C-terminal residues.
  • An extended helical structure within N-CoR-ID3 likely facilitates TR-specific binding.
  • N-CoR-ID3 may serve as a common interaction module for TR and other NRs like RevErb.

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