Figure 5.

Dynamic properties of the ETS and PNT domains regulate ETS1 function. (a) ETS1 autoinhibition involves a conformational equilibrium between a rigid inactive state and a flexible active state. Upon DNA binding, helix HI-1 unfolds. Transient phosphorylation-dependent interactions of the unstructured serine-rich region (SRR) with the regulatable unit, formed by the core ETS domain (red) and the appended inhibitory module (cyan), stabilize the inactive state (80). This stabilization increases progressively with increasing levels of CaM kinase II multisite phosphorylation of the SRR, leading to rheostatic control of ETS1 DNA binding (79). (b) The PNT domain of ETS1 interacts with the TAZ1 domain of CBP. Phosphorylation of ETS1 causes a conformational change and increases the affinity of the interaction (97). The ETS1 PNT domain consists of a core helical bundle (green) with appended helices H0 and H1 (orange). MAP kinase phosphorylation of Thr38 and Ser41 shifts a conformational equilibrium of the dynamic helix H0 toward a more open state. This conformational switch, along with increased complementary electrostatic interactions, favors binding of the TAZ1 domain (yellow). Note that the structure of the PNT-TAZ1 complex has not been determined, and though not shown in panel a or b, both the unmodified and phosphorylated forms of ETS1 can bind CBP and DNA, respectively.