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.
(2023) Structure 31: 1441
- PubMed: 37683642
- DOI: https://doi.org/10.1016/j.str.2023.08.013
- Primary Citation of Related Structures:
8JKL, 8JKN, 8JKO, 8JKQ, 8JKS
- 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 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 .
State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China. Electronic address: email@example.com.