Thresholds and ultrasensitivity from negative cooperativity

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Science  20 May 2016:
Vol. 352, Issue 6288, pp. 990-993
DOI: 10.1126/science.aad5937

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The secrets of making signaling responsive

Many receptor proteins that respond to biological signals form multimeric complexes, which gives them more sophisticated regulatory properties than those of simple one-to-one binding reactions. Ha et al. describe how the binding of multiple ligands to receptor complexes can generate threshold effects and switch-like ultrasensitivity. If binding of the first ligand makes binding of a second less likely (a property known as negative cooperativity), and binding can also deplete the total amount of ligand present, the way the system responds to various doses of the ligand can change dramatically from a very gradual one to a switch-like behavior. The authors provide theory and experiments that explain how such systems function and may be suited to biological regulation.

Science, this issue p. 990


Negative cooperativity is a phenomenon in which the binding of one or more molecules of a ligand to a multimeric receptor makes it more difficult for subsequent ligand molecules to bind. Negative cooperativity can make a multimeric receptor’s response more graded than it would otherwise be. However, through theory and experimental results, we show that if the ligand binds the receptor with high affinity and can be appreciably depleted by receptor binding, then negative cooperativity produces a qualitatively different type of response: a highly ultrasensitive response with a pronounced threshold. Because ultrasensitivity and thresholds are important for generating various complex systems-level behaviors, including bistability and oscillations, negative cooperativity may be an important ingredient in many types of biological responses.

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