Circadian Interactomics: How Research Into Protein-Protein Interactions Beyond the Core Clock Has Influenced the Model of Circadian Timekeeping

Abstract

The circadian clock is the broadly conserved, protein-based, timekeeping mechanism that synchronizes biology to the Earth's 24-h light-dark cycle. Studies of the mechanisms of circadian timekeeping have placed great focus on the role that individual protein-protein interactions play in the creation of the timekeeping loop. However, research has shown that clock proteins most commonly act as part of large macromolecular protein complexes to facilitate circadian control over physiology. The formation of these complexes has led to the large-scale study of the proteins that comprise these complexes, termed here "circadian interactomics." Circadian interactomic studies of the macromolecular protein complexes that comprise the circadian clock have uncovered many basic principles of circadian timekeeping as well as mechanisms of circadian control over cellular physiology. In this review, we examine the wealth of knowledge accumulated using circadian interactomics approaches to investigate the macromolecular complexes of the core circadian clock, including insights into the core mechanisms that impart circadian timing and the clock's regulation of many physiological processes. We examine data acquired from the investigation of the macromolecular complexes centered on both the activating and repressing arm of the circadian clock and from many circadian model organisms.

Keywords: Arabidopsis; Drosophila; Neurospora; cyanobacteria; interactomics; macromolecular protein complexes.

Figure 1.

The protein-based timing mechanisms of the circadian clock are evolutionarily conserved. A simplified diagrammatic representation of the core circadian clock proteins across many circadian model organisms. The central mechanism consists of positive elements that activate the negative elements, which in turn act to repress the activation by the positive elements. Core clock components from each model system are represented in their associated feedback loops.

Figure 2.

Circadian negative arm complexes aid in the regulation of many cellular processes. A pictorial illustration of cellular processes that the negative arm has been linked to based on circadian interactomics data. The organisms in which these discoveries were made are represented next to each cellular process.

Figure 3.

Proteins in the positive arm of the circadian clock form complexes that control circadian timing and output. A graphic depiction of the elements of cellular physiology that have been linked to the positive arm of the clock based on circadian protein interactomics studies. The organisms in which these discoveries were made are represented next to each cellular process.