Deciphering the regulation mechanism in biochemical networks by a systems-biology approach

Abstract

To decipher molecular mechanisms in biological systems from system-level input-output data is challenging especially for complex processes that involve interactions among multiple components. Here, we study regulation of the multi-domain (P1-5) histidine kinase CheA by the MCP chemoreceptors. We develop a network model to describe dynamics of the system treating the receptor complex with CheW and P3P4P5 domains of CheA as a regulated enzyme with two substrates, P1 and ATP. The model enables us to search the hypothesis space systematically for the simplest possible regulation mechanism consistent with the available data. Our analysis reveals a novel dual regulation mechanism wherein besides regulating ATP binding the receptor activity has to regulate one other key reaction, either P1 binding or phosphotransfer between P1 and ATP. Furthermore, our study shows that the receptors only control kinetic rates of the enzyme without changing its equilibrium properties. Predictions are made for future experiments to distinguish the remaining two dual-regulation mechanisms. This systems-biology approach of combining modeling and a large input-output data-set should be applicable for studying other complex biological processes.