Fig. 1

Conservation of the Core Clock Architecture. a The Transcription-Translation Negative Feedback Loop (TTFL) in fungi and animals comprises two main complexes. The first is a pair of heterodimeric activators known as the positive arm complex (green diamond) and the second, a repressing negative arm complex (red hexagon). The positive arm drives the expression of genes encoding negative arm components leading to the transcription and translation of the negative arm proteins. The negative arm proteins complex with kinases and are post-translationally modified by phosphorylation (shown as yellow stars), enabling negative arm repression of the positive arm. Distinct phospho-states trigger both positive-arm repression (blunted arrow) and negative-arm protein instability (represented by the faded red hexagon). Phosphorylation-related turnover is not necessary to close the loop in fungi, where this has been examined most closely, but instead represents cellular good housekeeping, cleaning up proteins that are no longer useful. When active, the positive arm also promotes the expression of clock-controlled genes (ccgs), which are predicted to control circadian output (reviewed [15]) b In the mammalian clock, positive arm-proteins Brain and Muscle ARNT-Like 1 (BMAL1, also known as ARNTL) and Circadian Locomotor Output Cycles Kaput (CLOCK) form a complex to activate the negative-arm PERIODs (PER1, PER2, and PER3) in addition to CRYPTOCHROMEs (CRY1 and CRY2). PERs and CRYs complex with several kinases to repress CLOCK:BMAL activity [16]. In the Neurospora clock, the positive heterodimer complex is comprised of White Collar-1 (WC-1) and White Collar-2 (WC-2) which together form the White Collar Complex (WCC). WCC drives the expression of the negative arm component FREQUENCY (FRQ), which, with its essential binding partner FREQUENCY-Interacting RNA Helicase (FRH), associates with the kinase Casein Kinase-1 (CK-1a) forming the FRQ-FRH Complex (FFC) [23, 24]. The positive-arm constituents in the Drosophila clock are CYCLE (CYC) and dClk, while the negative arm components are PERIOD (dPER), TIMELESS (TIM) and casein kinase 1, called DOUBLETIME (DBT) in Drosophila [25]. Figure 1b was created using BioRender.com