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.

Conformational Changes in the Negative Arm of the Circadian Clock Correlate with Dynamic Interactomes Involved in Post-transcriptionally Regulated Processes

“…Regardless of the mechanism by which the negative arm imparts post-transcriptional regulation, FRQ, dPER, and hPER have extensive interactomes, with functions that range across diverse gene ontologies (Figure 4). This aligns with the large and variable interactomes that are a hallmark of negative-arm proteins throughout eukaryotic circadian clocks 23,27,31,[95][96][97][98] . In FRQ, we found that 58 interactors, more than half of which (33) were IDPs, have rhythmic proteins without corresponding rhythmic mRNA.…”

“…Beyond negative arm repression of the positive arm, the role of the negative arm in the regulation of output, if any, is not clear. What is known is that the negative arm forms a multitude of macromolecular complexes with a variety of proteins, including many that do not play a direct role in timekeeping [21][22][23][24] . This paradigm is true in the TTFL of fungal, insect, and mammalian cells, where the core negative arm proteins, FREQUENCY in fungi (FRQ) and the PERIODs in animals (PERs) have been demonstrated to have a wide array of interactors, only some of which impact core clock functions 21,23,[25][26][27][28] .…”

“…What is known is that the negative arm forms a multitude of macromolecular complexes with a variety of proteins, including many that do not play a direct role in timekeeping [21][22][23][24] . This paradigm is true in the TTFL of fungal, insect, and mammalian cells, where the core negative arm proteins, FREQUENCY in fungi (FRQ) and the PERIODs in animals (PERs) have been demonstrated to have a wide array of interactors, only some of which impact core clock functions 21,23,[25][26][27][28] . The conservation of large interactomes in negative-arm clock proteins is not surprising as negative-arm proteins from eukaryotic clocks are largely intrinsically disordered proteins (IDPs) 6,[29][30][31][32][33] .…”

The circadian clock controls temporal and spatial patterns of floral development in sunflower

“…Thus in both plants and animals, internal body clocks can generate serially repeated organs. These types of clocks are distinct from the circadian oscillator, the biological clock found in most eukaryotes and some prokaryotes ( Mosier and Hurley, 2021 ). Circadian clocks coordinate development on daily and seasonal time scales.…”

Network Analysis of Effect of Light-Dark Time Ratio on the Gene Expression Profile of Mouse Skin

“…This timekeeping mechanism is based on largely conserved proteins. 3 Cryptochrome-1 (Cry-1) and cryptochrome-2 (Cry-2) are mammalian proteins that belong to the family of plant blue-light receptors (cryptochromes). Cry-1 and Cry-2 are known as core clock components.…”