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Unusual Rel-like architecture in the DNA-binding domain of the transcription factor NFATc

S A Wolfe1, P Zhou, V Dötsch

  • 1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

Nature
|January 9, 1997
PubMed

Insights

Researchers identified the NFATc DNA-binding domain (NFATc-DBD), crucial for immune response regulation. This discovery aids in developing new drugs targeting NFAT directly, potentially reducing immunosuppressive therapy side effects.

Area of Science:

  • Molecular Biology
  • Immunology
  • Structural Biology

Background:

  • Nuclear factor of activated T-cells (NFAT) proteins regulate immune responses.
  • Current immunosuppressants like FK506 and cyclosporin A (CsA) target NFAT signaling but cause toxic side effects.
  • Direct NFAT antagonists could offer safer alternatives.

Purpose of the Study:

  • To identify and characterize the DNA-binding domain of NFATc (NFATc-DBD).
  • To determine the solution structure of NFATc-DBD for structure-based drug design.
  • To understand NFAT's DNA binding and transcriptional activation mechanisms.

Main Methods:

  • Protein expression and purification of NFATc-DBD.
  • Nuclear Magnetic Resonance (NMR) spectroscopy for structure determination.
  • Comparative structural analysis with NF-kappaB p50.

Main Results:

  • The 20 kDa NFATc-DNA binding domain (NFATc-DBD) was identified as necessary and sufficient for DNA binding and transcriptional activation.
  • The solution structure of NFATc-DBD was determined.
  • NFATc-DBD employs a distinct DNA recognition strategy compared to NF-kappaB p50.
  • A model for the cooperative complex of NFAT and AP-1 on the interleukin-2 enhancer was proposed.

Conclusions:

  • The NFATc-DBD structure provides a basis for designing novel NFAT-targeted immunosuppressants.
  • Understanding NFAT's DNA binding mechanism is key to developing safer therapeutic strategies.
  • This work facilitates the development of antagonists with potentially reduced toxicity compared to current drugs.

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