Ultrasensitive response motifs: basic amplifiers in molecular signalling networks

Abstract

Multi-component signal transduction pathways and gene regulatory circuits underpin integrated cellular responses to perturbations. A recurring set of network motifs serve as the basic building blocks of these molecular signalling networks. This review focuses on ultrasensitive response motifs (URMs) that amplify small percentage changes in the input signal into larger percentage changes in the output response. URMs generally possess a sigmoid input–output relationship that is steeper than the Michaelis–Menten type of response and is often approximated by the Hill function. Six types of URMs can be commonly found in intracellular molecular networks and each has a distinct kinetic mechanism for signal amplification. These URMs are: (i) positive cooperative binding, (ii) homo-multimerization, (iii) multistep signalling, (iv) molecular titration, (v) zero-order covalent modification cycle and (vi) positive feedback. Multiple URMs can be combined to generate highly switch-like responses. Serving as basic signal amplifiers, these URMs are essential for molecular circuits to produce complex nonlinear dynamics, including multistability, robust adaptation and oscillation. These dynamic properties are in turn responsible for higher-level cellular behaviours, such as cell fate determination, homeostasis and biological rhythm.

Supramolecular Buffering by Ring–Chain Competition

“…Ultrasensitive threshold behavior can be generated by various molecular mechanisms, such as positive feedback or molecular titration. 35 In the latter case, active components are stoichiometrically sequestered by reversible binding to strong inhibitors up until the equivalence point set by the concentration of the inhibitor. 12c,36 Once the inhibitor sink is filled, an increase in the total concentration of active component then results in a steep increase in the concentration of free active monomer ( Figure 7C).…”

Intrinsic disorder as a generalizable strategy for the rational design of highly responsive, allosterically cooperative receptors

“…ultrasensitivity | intrinsically disordered proteins | biosensors | synthetic biology | ribozymes T he ability to control the shape and midpoint of binding curves is critical to nature's ability to optimize many cellular processes (1). One of the most widely used mechanisms by which nature so tunes the behavior of her receptors is allostery, in which the binding of one ligand alters the affinity with which subsequent ligands bind.…”

Three level signal transduction cascades lead to reliably timed switches

“…Functional and evolutionary studies of such cascades tend to emphasize their role as amplifiers of some input signal. Koshland et al [2] 15 (see also [3]) observe that "amplification" in this context involves at least two distinct notions: amplification of the absolute size of the signal and amplification of the change in signal intensity relative to the signal background intensity, so-called "fold" amplification [4]. Classic examples of the former include blood clotting [5,6,7,8] and complement [9,10] among others probably evolved from 20 the same ancestral serine protease cascade [11].…”

“…In both general cases, amplification is generated by layering in the cascade. Layering can also produce ultrasensitive responses, in which smooth changes in input are converted to a switch-like "off-on" output 25 with a steeper signal-to-response curve than seen with traditional MichaelisMenten dynamics [14,15,16,2,17,3].…”