ArticleThe Journal of biological chemistry2024
Hierarchical and scaffolded phosphorylation of two degrons controls PER2 stability.
Article in The Journal of biological chemistry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Time matters: circadian genetics and the molecular logic of human health and disease.Nature reviews. Genetics · 2026Review
- The role of sleep disorders in orchestrating proteomic dysfunction and multi-morbidity.Molecular psychiatry · 2026Review
- Disordered but rhythmic-the role of intrinsic protein disorder in eukaryotic circadian timing.FEBS letters · 2026Review
- Markovian state models uncover casein kinase 1 dynamics that govern circadian period.Biophysical journal · 2025Article
- PERspectives on circadian cell biology.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2025Review
- Isoform-specific C-terminal phosphorylation drives autoinhibition of Casein kinase 1.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Isoform-specific C-terminal phosphorylation drives autoinhibition of Casein Kinase 1.bioRxiv : the preprint server for biology · 2024Article
Corrections and comments
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Authors and funding
2 authors.
Funding
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Abstract
The duration of the transcription-repression cycles that give rise to mammalian circadian rhythms is largely determined by the stability of the PERIOD (PER) protein, the rate-limiting components of the molecular clock. The degradation of PERs is tightly regulated by multisite phosphorylation by casein kinase 1 (CK1δ/ε). In this phosphoswitch, phosphorylation of a PER2 degron [degron 2 (D2)] causes degradation, while phosphorylation of the PER2 familial advanced sleep phase (FASP) domain blocks CK1 activity on the degron, stabilizing PER2. However, this model and many other studies of PER2 degradation do not include the second degron of PER2 that is conserved in PER1, termed degron 1 (D1). We examined how these two degrons contribute to PER2 stability, affect the balance of the phosphoswitch, and how they are differentiated by CK1. Using PER2-luciferase fusions and real-time luminometry, we investigated the contribution of both D2 and of CK1-PER2 binding. We find that D1, like D2, is a substrate of CK1 but that D1 plays only a 'backup' role in PER2 degradation. Notably, CK1 bound to a PER1:PER2 dimer protein can phosphorylate PER1 D1 in trans. This scaffolded phosphorylation provides additional levels of control to PER stability and circadian rhythms.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.