Bayesian modeling reveals metabolite‐dependent ultrasensitivity in the cyanobacterial circadian clock
Year: 2020
Type: article
Abstract: Mathematical models can enable a predictive understanding of mechanism in cell biology by quantitatively describing complex networks of interactions, but such models are often poorly constrained by available data. Owing to its relative biochemical simplicity, the core circadian oscillator in Synechococcus elongatus has become a prototypical system for studying how collective dynamics emerge from molecular interactions. The oscillator consists of only three proteins, KaiA, KaiB, and KaiC, and near-24-h cycles of KaiC phosphorylation can be reconstituted in vitro. Here, we formulate a molecularly-detailed but mechanistically agnostic model of the KaiA-KaiC subsystem and fit it directly to experimental data within a Bayesian parameter estimation framework. Analysis of the fits consistently reveals an ultrasensitive response for KaiC phosphorylation as a function of KaiA concentration, which we confirm experimentally. This ultrasensitivity primarily results from the differential affinity of KaiA for competing nucleotide-bound states of KaiC. We argue that the ultrasensitive stimulus-response relation is critical to metabolic compensation by suppressing premature phosphorylation at nighttime. Synopsis This study takes a data-driven kinetic modeling approach to characterizing the interaction between KaiA and KaiC in the cyanobacterial circadian oscillator and understanding how the oscillator responds to changes in cellular metabolic conditions. An extensive dataset of KaiC autophosphorylation measurements was gathered and fit to a detailed yet mechanistically agnostic kinetic model within a Bayesian parameter estimation framework. KaiA concentration tunes the sensitivity of KaiC autophosphorylation and the period of the full oscillator to %ATP. The model reveals an ultrasensitive dependence of KaiC phosphorylation on KaiA concentration as a result of differential KaiA binding affinity to ADP- vs. ATP-bound KaiC. Ultrasensitivity in KaiC phosphorylation contributes to metabolic compensation by suppressing premature phosphorylation at nighttime.
Source: Molecular Systems Biology
Authors: Lu Hong, Danylo O Lavrentovich, Archana Chavan, Eugene Leypunskiy, Eileen Li, Charles Matthews, Andy LiWang, Michael J Rust, Aaron R Dinner
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,600
Awards: Using systematic computational approaches to elucidate the molecular and network dynamics underlying a circadian clock, G1527651137, G1742171491, G1931640610, The Linchpin that Joins the Circadian Oscillator to Clock Output, G2206590661, G2419406149, G3226045097, G3268722540, XSEDE 2.0: Integrating, Enabling and Enhancing National Cyberinfrastructure with Expanding Community Involvement, G3812616897, CREST Center for Cellular and Biomolecular Machines, A systems-level study of signaling networks and differentiation, G4806795785, G5178997392, Robust rare event simulation for protein folding and disease-related aggregation, G6806689448, Coupling between Circadian Rhythms and Metaboilsm in Cyanobacteria, G7342799080, The Biochemistry of Clock Function in Fluctuating Environments, ENSEMBLE SIMULATION TECHNIQUES AND FAST RANDOMIZED AIGORITHMS, G969889393
OpenAlex ID: W3032215097