New Theory Suggests That Negative Cooperativity Can Make A Switch-Life Response In Signaling

The standard theory on negative cooperativity where the binding of one ligand makes it harder for a second ligand to bind to multi-subunit receptors says that the higher the negative cooperativity, the more graded the receptor’s response. It turns out that there is a little algebraic shortcut built into the standard theory, but in many situations, especially intracellular signaling, this assumption does not hold.

In this work, Drs. Sanghoon Ha and James Ferrell re-derived the theory without this shortcut, and found that the results defy expectation. Negative cooperativity can endow a receptor’s response with a marked threshold, making it so that there will be no response until the ligand concentration is high enough to occupy half of the binding sites. This property can allow a receptor to filter out small inputs and then respond decisively to inputs above the threshold value. Drs. Ha and Ferrell went onto to test their new theory with a series of synthetic biology experiments and found that their results are in beautiful agreement with the new theory.

This new theory may have wide applicability since the literature reports that a number of receptors exhibit strong negative cooperativity in their ligand binding. It would be very interesting to know whether those receptors end up with thresholds in their responses as a result.

Ha SH and Ferrell JE Jr. Thresholds and ultrasensitivity from negative cooperativity.  Science 2016 May 20;352: 990–993, PMID:27174675 [PubMed]