8JKS

T95R mutant IRF4 DNA-binding domain bound to an DNA containing GAGA motif

Summary for 8JKS

• Entry DOI: 10.2210/pdb8jks/pdb
• Descriptor: GAGA-Forward, GAGA-Reverse, Interferon regulatory factor 4 (3 entities in total)
• Functional Keywords: irf4, transcription factor, protein-dna complex, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 77887.08

Authors

Wang, G.,Feng, X.,Ding, J. (deposition date: 2023-06-01, release date: 2023-09-20, Last modification date: 2023-11-15)

Primary citation

Wang, G.,Feng, X.,Ding, J.
Molecular basis for the functional roles of the multimorphic T95R mutation of IRF4 causing human autosomal dominant combined immunodeficiency.
Structure, 31:1441-, 2023

PubMed Abstract: Interferon regulatory factor 4 (IRF4) is a transcription factor that regulates the development and function of immune cells. Recently, a new multimorphic mutation T95R was identified in the IRF4 DNA-binding domain (DBD) in patients with autosomal dominant combined immune deficiency. Here, we characterized the interactions of the wild-type IRF4-DBD (IRF4-DBD) and T95R mutant (IRF4-DBD) with a canonical DNA sequence and several noncanonical DNA sequences. We found that compared to IRF4-DBD, IRF4-DBD exhibits higher binding affinities for both canonical and noncanonical DNAs, with the highest preference for the noncanonical GATA sequence. The crystal structures of IRF4-DBD in complex with the GATA sequence and IRF4-DBD in complexes with both canonical and noncanonical DNAs were determined, showing that the T95R mutation enhances the interactions of IRF4-DBD with the canonical and noncanonical DNAs to achieve higher affinity and specificity. Collectively, our data provide the molecular basis for the gain-of-function and new function of IRF4.

PubMed: 37683642
DOI: 10.1016/j.str.2023.08.013

Experimental method

X-RAY DIFFRACTION (3.3 Å)