Understanding the basis of the DNA-binding specificity of transcription factors (TFs) has been of long-standing interest. Despite extensive efforts to map millions of putative TF binding sequences, identifying the critical determinants for DNA binding specificity remains a major challenge. The coevolution of residues in proteins occurs due to a shared evolutionary history. However, it is unclear how coevolving residues in TFs contribute to DNA binding specificity. Here, we systematically collected publicly available datasets from multiple large-scale high-throughput TF–DNA interaction screening experiments for the major TF families with large numbers of TF members. These families included the homeobox, HLH, bZIP_1, Ets, HMG_box, ZF-C4, and Zn_clus TFs. We detected TF subclass determining sites (TSDSs) and showed that the TSDSs were more likely to coevolve with other TSDSs than with non-TSDSs, particularly for the Homeobox, HLH, Ets, bZIP_1, and HMG_box TF families. By in silico modeling, we showed that mutation of the highly coevolving residues could significantly reduce the stability of the TF–DNA complex. The distant residues from the DNA interface also contributed to TF–DNA binding activity. Overall, our study gave evidence that coevolved residues relate to transcriptional regulation and provided insights into the potential application of engineered DNA-binding domains and proteins.
Luan Y, Tang Z, He Y, et al. Intra-Domain Residue Coevolution in Transcription Factors Contributes to DNA Binding Specificity[J]. Microbiology spectrum, 11(2): e0365122.
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