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Native Polyacrylamide Gel Electrophoresis Immunoblot Analysis of Endogenous IRF5 Dimerization
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Structural determinants of the IRF4/DNA homodimeric complex.

Srinivasan Sundararaj1, Sandali Seneviratne1, Simon J Williams2

  • 1Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra 2600, Australia.

Nucleic Acids Research
|February 3, 2021
PubMed
Summary

Interferon regulatory factor 4 (IRF4) forms distinct DNA complexes. Structural analysis reveals key differences between IRF4 homodimers and heterodimers, impacting immune cell transcriptional regulation and offering insights into chronic lymphocytic leukemia.

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Area of Science:

  • Molecular Biology
  • Structural Biology
  • Immunology

Background:

  • Interferon regulatory factor 4 (IRF4) is a crucial transcription factor (TF) regulating immune cells like B and T cells.
  • IRF4 functions through DNA binding as both homodimers and heterodimers with other TFs, influencing transcriptional programs and cell fate.
  • Understanding the structural basis of IRF4's homo- and heterodimeric interactions is vital for deciphering its regulatory roles.

Purpose of the Study:

  • To determine the crystal structure of the IRF4/ISRE homodimeric complex.
  • To elucidate the molecular mechanisms underlying IRF4's homo- and heterodimeric DNA binding.
  • To investigate the structural basis of IRF4 mutations associated with chronic lymphocytic leukemia.

Main Methods:

  • X-ray crystallography was employed to determine the structure of the IRF4/ISRE homodimeric complex.
  • Comparative analysis of homo- and heterodimeric IRF4-DNA interactions.
  • Characterization of DNA binding properties of wild-type and mutant IRF4 (IRF4L116R).

Main Results:

  • The IRF4 homodimeric complex formation involves significant DNA deformation and cooperative binding solely through protein-DNA contacts.
  • Hotspot residues (Arg98, Cys99, Asn102) interact with both consensus and non-consensus DNA sequences, with a flexible L1 loop.
  • The IRF4L116R mutant, linked to chronic lymphocytic leukemia, exhibits enhanced DNA binding, explaining its gain-of-function.

Conclusions:

  • Key structural distinctions exist between IRF4 homo- and heterodimeric complexes.
  • These structural differences provide molecular insights into IRF4-mediated transcriptional regulation in immune cells.
  • The findings offer a structural rationale for the role of IRF4 mutations in chronic lymphocytic leukemia pathogenesis.