Figure 8. Signaling activity versus thermodynamic stability.

A conceptual relationship between the thermodynamic stability and signaling activity of Ras variants is shown. A decrease in stability can increase signaling activity by enhancing nucleotide-exchange rates or compromising catalytic activity. However, further stability reduction reaches the stability threshold. The stability threshold buffers the deleterious effects of mutations (Bershtein et al., 2006), and is epistatic in nature; once exhausted, the deleterious effects of mutations become fully pronounced. Hence, signaling activity decreases. The closer a mutant is to the stability threshold, the narrower the window where the mutant can promote hyperactivation in vivo.