Allosteric autoactivation of SOS and its kinetic mechanism.

Hanh My Hoang, Hope Gloria Umutesi, Jongyun Heo

Small GTPases 2021 Jan

filter terms:

Son of Sevenless (SOS), one of guanine nucleotide exchange factors (GEFs), activates Ras. We discovered that the allosteric domain of SOS yields SOS to proceed a previously unrecognized autoactivation kinetics. Its essential feature is a time-dependent acceleration of SOS feedback activation with a reaction initiator or with the priming of active Ras. Thus, this mechanistic autoactivation feature explains the notion, previously only conjectured, of accelerative SOS activation followed by the priming of active Ras, an action produced by another GEF Ras guanyl nucleotide-releasing protein (RasGRP). Intriguingly, the kinetic transition from gradual RasGRP activation to accelerative SOS activation has been interpreted as an analog to digital conversion; however, from the perspective of autoactivation kinetics, it is a process of straightforward RasGRP-mediated SOS autoactivation. From the viewpoint of allosteric protein cooperativity, SOS autoactivation is a unique time-dependent cooperative SOS activation because it enables an active SOS to accelerate activation of other SOS as a function of time. This time-dependent SOS cooperativity does not belong to the classic steady-state protein cooperativity, which depends on ligand concentration. Although its hysteretic or sigmoid-like saturation curvature is a classic hallmark of steady-state protein cooperativity, its hyperbolic saturation figure typically represents protein noncooperativity. We also discovered that SOS autoactivation perturbs the previously predicted hysteresis of SOS activation in a steady state to produce a hyperbolic saturation curve. We interpret this as showing that SOS allostery elicits, through SOS autoactivation, cooperativity uniquely time-dependent but not ligand concentration dependent.