The transcription factor ASCIZ (ATMIN, ZNF822) has an unusually high number of recognition motifs for the product of its main target gene, the hub protein LC8 (DYNLL1). Using a combination of biophysical methods, structural analysis by NMR and electron microscopy, and cellular transcription assays, we developed a model that proposes a concerted role of intrinsic disorder and multiple LC8 binding events in regulating LC8 transcription. We demonstrate that the long intrinsically disordered C-terminal domain of ASCIZ binds LC8 to form a dynamic ensemble of complexes with a gradient of transcriptional activity that is inversely proportional to LC8 occupancy. The preference for low occupancy complexes at saturating LC8 concentrations with both human and Drosophila ASCIZ indicates that negative cooperativity is an important feature of ASCIZ-LC8 interactions. The prevalence of intrinsic disorder and multivalency among transcription factors suggests that formation of heterogeneous, dynamic complexes is a widespread mechanism for tuning transcriptional regulation.

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Biochemistry and Biophysics Oregon State University Oregon United States

Department of Chemistry Portland State University Oregon United States

Department of Medicine St Vincent's Health The University of Melbourne Victoria Australia

School of Biological Sciences University of Canterbury Christchurch New Zealand

St Vincent's Institute of Medical Research The University of Melbourne Victoria Australia

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Elife. 2018 Aug 03;7:e40684. doi: 10.7554/eLife.40684. PubMed

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