Zinc controls operator affinity of human transcription factor YY1 by mediating dimerization via its N-terminal region.

Human protein Yin Yang 1 (YY1) controls the transcription of hundreds of genes both positively and negatively through interactions with a wide range of partner proteins. Results presented here from proteolytic sensitivity, calorimetry, circular dichroism, fluorescence, NMR, size-exclusion chromatography, SELEX, and EMSA show that purified YY1 forms dimers via its disordered N-terminal region with strong zinc-ion concentration dependence. The YY1 dimer is shown to bind tandem repeats of a canonical recognition DNA sequence with high affinity, and analysis of human YY1 regulatory sites shows that many contain repeats of its recognition elements. YY1 dimerization may compete with partner protein interactions, making control by zinc ion concentration a previously unrecognized factor affecting YY1 gene regulation. Indeed, YY1 is known to be important in many pathogenic processes, including neoplasia, in which zinc ion concentrations are altered. The present results incentivize studies in vivo or in vitro that explore the role of zinc ion concentration in YY1-mediated gene expression.

The transcription factor YY2 has less momentous properties of an intrinsically disordered protein than its paralog YY1.

The transcription factor YY2 is a recently discovered paralog of YY1. The two proteins exhibit substantial sequence similarity and partially similar transcriptional activity. They recognize the same DNA sequence in vitro yet bind different promoters in vivo. YY1 comprises two structurally distinct parts: an intrinsically disordered regulatory part and a compact DNA-binding domain. The structure of YY2 is yet unknown. We show that YY2 is structurally similar to YY1, although the conformational state of YY2 is more ordered, as shown by its composition, hydrodynamic properties, spectroscopic signal, and proteolytic susceptibility. As such, YY2's range of molecular partners might be distinct from that of YY1. This could explain different effects of YY1 and YY2 on gene expression patterns and the mechanism of YY proteins in transcriptional regulation.