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T95R mutant IRF4 DNA-binding domain bound to an DNA containing GATA motifT95R mutant IRF4 DNA-binding domain bound to an DNA containing GATA motif
Structural highlights
FunctionPublication Abstract from PubMedInterferon 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(WT)) and T95R mutant (IRF4-DBD(T95R)) with a canonical DNA sequence and several noncanonical DNA sequences. We found that compared to IRF4-DBD(WT), IRF4-DBD(T95R) 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(WT) in complex with the GATA sequence and IRF4-DBD(T95R) in complexes with both canonical and noncanonical DNAs were determined, showing that the T95R mutation enhances the interactions of IRF4-DBD(T95R) 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(T95R). Molecular basis for the functional roles of the multimorphic T95R mutation of IRF4 causing human autosomal dominant combined immunodeficiency.,Wang G, Feng X, Ding J Structure. 2023 Aug 31:S0969-2126(23)00293-9. doi: 10.1016/j.str.2023.08.013. PMID:37683642[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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