{"doi":"10.7554/elife.55275","title":"Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing","abstract":"Mammalian circadian rhythms are generated by a transcription-based feedback loop in which CLOCK:BMAL1 drives transcription of its repressors (PER1/2, CRY1/2), which ultimately interact with CLOCK:BMAL1 to close the feedback loop with ~24 hr periodicity. Here we pinpoint a key difference between CRY1 and CRY2 that underlies their differential strengths as transcriptional repressors. Both cryptochromes bind the BMAL1 transactivation domain similarly to sequester it from coactivators and repress CLOCK:BMAL1 activity. However, we find that CRY1 is recruited with much higher affinity to the PAS domain core of CLOCK:BMAL1, allowing it to serve as a stronger repressor that lengthens circadian period. We discovered a dynamic serine-rich loop adjacent to the secondary pocket in the photolyase homology region (PHR) domain that regulates differential binding of cryptochromes to the PAS domain core of CLOCK:BMAL1. Notably, binding of the co-repressor PER2 remodels the serine loop of CRY2, making it more CRY1-like and enhancing its affinity for CLOCK:BMAL1.","journal":"eLife","year":2020,"id":57736,"datarank":2.0304263504741193,"base_score":4.343805421853684,"endowment":4.343805421853684,"self_citation_contribution":0.6515708132780527,"citation_network_contribution":1.378855537196067,"self_endowment_contribution":0.6515708132780527,"citer_contribution":1.378855537196067,"corpus_percentile":null,"corpus_rank":null,"citation_count":76,"citer_count":53,"citers_with_citation_signal":45,"citers_with_endowment":45,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9481,"is_data_producer":true,"deposit_databanks":{"PDB":["6OF7"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":301885,"name":"Ashutosh Srivastava","orcid":"0000-0001-9820-720X","position":1,"is_corresponding":false},{"id":301886,"name":"Colby R. Sandate","orcid":"0000-0002-8758-5931","position":2,"is_corresponding":false},{"id":301887,"name":"Alicia K. Michael","orcid":"0000-0002-6080-839X","position":3,"is_corresponding":false},{"id":58019,"name":"Peter Hsu","orcid":"0000-0002-9381-6564","position":4,"is_corresponding":false},{"id":301888,"name":"Christin Rakers","orcid":"0000-0002-5668-6844","position":5,"is_corresponding":false},{"id":301889,"name":"Leslee T. Nguyen","orcid":"0000-0002-6750-4575","position":6,"is_corresponding":false},{"id":303333,"name":"Megan R Torgrimson","orcid":null,"position":7,"is_corresponding":false},{"id":301890,"name":"Gian Carlo G. Parico","orcid":"0000-0002-7110-403X","position":8,"is_corresponding":false},{"id":285738,"name":"Sarvind Tripathi","orcid":"0000-0002-6959-0577","position":9,"is_corresponding":false},{"id":6649,"name":"Ning Zheng","orcid":"0000-0002-1039-1581","position":10,"is_corresponding":false},{"id":287919,"name":"Gabriel C. Lander","orcid":"0000-0003-4921-1135","position":11,"is_corresponding":false},{"id":301891,"name":"Tsuyoshi Hirota","orcid":"0000-0003-4876-3608","position":12,"is_corresponding":false},{"id":301892,"name":"Florence Tama","orcid":"0000-0003-2021-5618","position":13,"is_corresponding":false},{"id":285740,"name":"Carrie L. Partch","orcid":"0000-0002-4677-2861","position":14,"is_corresponding":false},{"id":301884,"name":"Jennifer L. Fribourgh","orcid":"0000-0001-5954-4991","position":0,"is_corresponding":true}],"reference_count":73,"raw_metadata":null,"created_at":"2026-07-18T21:06:48.611399Z","pmid":"32101164","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}