Structure and Function of a Transcriptional ‘Accelerator’ Circuit

Abstract

Biological signaling circuits, like electrical circuits, face a fundamental tradeoff between speed and amplitude: faster rates of initial increase are typically obtained at the cost of a higher steady-state level. This creates an evolutionary tradeoff when rapid signaling is essential but the signaling molecule is cytotoxic at high levels (e.g. for fever response, inflammatory cytokines, and many viruses). We recently discovered a transcriptional circuit in a human herpesvirus (CMV) that overcomes this tradeoff - and confers significant fitness to the virus - by converting signaling inputs into faster expression rates without amplifying final equilibrium levels in individual cells (Teng et al. Cell, 2012).Strikingly, the accelerator circuit maps to a transcriptional negative-feedback loop encoding an exceptionally high self cooperativity (Hill coefficient ≈ 7). Binding of the virus's essential transactivator protein, IE2, to a single 14-bp sequence in its own promoter generates negative auto-regulation but how such a high Hill coefficient was generated remained unclear.Here, we report biophysical and structural studies of the IE2-DNA interaction showing a novel homo-multimer structure accounts for Hill coefficient ∼ 7. In general, such accelerator circuits may provide a mechanism for signal-transduction circuits to respond quickly to external signals without increasing steady-state levels of potentially cytotoxic molecules.