Intrinsic disorder: signaling via highly specific but short-lived association

Association between signaling proteins and their cellular targets is generally thought to be highly specific (implicating a high association constant, Ka) and, at the same time, transient or short-lived (corresponding to a high dissociation rate constant, kd). However, a combination of high Ka and high kd would lead to a high association rate constant (ka = Kakd), which poses a problem because there is a limit to which ka can be increased, set by the diffusional approach to form the complex. In this Opinion article, I propose that having the signaling protein disordered before binding to the target provides a way out of this quandary. The intrinsic disorder of the signaling protein would decrease Ka without sacrificing the specificity of the complex, and thus would allow kd to be increased to a range appropriate for signaling.