ArticleProceedings of the National Academy of Sciences of the United States of America2019
Heme binding to human CLOCK affects interactions with the E-box.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
29 citing papers in PubMed, 58 citations in OpenAlex.
- The CLOCK-BMAL1 complex in circadian regulation: structure, mechanisms, and therapeutic targeting.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Review
- Small Molecule Regulation of CLOCK:BMAL1 DNA Binding Activity.bioRxiv : the preprint server for biology · 2026Article
- Heme and CO metabolism by the canonical human heme oxygenases.Journal of inorganic biochemistry · 2026Review
- A reversible feedback mechanism regulating mitochondrial heme synthesis.The Journal of biological chemistry · 2026Article
- An extended network for regulation of heme homeostasis in cells.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- A reversible feedback mechanism regulating mitochondrial heme synthesis.bioRxiv : the preprint server for biology · 2025Article
- Regulation of gene expression through protein-metabolite interactions.npj metabolic health and disease · 2025Review
- Why cells need iron: a compendium of iron utilisation.Trends in endocrinology and metabolism: TEM · 2024Review
- Oxygen is an essential gasotransmitter directly sensed via protein gasoreceptors.Animal models and experimental medicine · 2024Article
- PAS Dimerization at the Nexus of the Mammalian Circadian Clock.Journal of molecular biology · 2024Review
- Per-ARNT-Sim (PAS) Domains in Basic Helix-Loop-Helix (bHLH)-PAS Transcription Factors and Coactivators: Structures and Mechanisms.Journal of molecular biology · 2024Review
- Gas-sensing riboceptors.RNA biology · 2024Article
- Role of TET1-mediated epigenetic modulation in Alzheimer's disease.Neurobiology of disease · 2023Article
- Origin and functional diversification of PAS domain, a ubiquitous intracellular sensor.Science advances · 2023Article
- CLOCK inhibits the proliferation of porcine ovarian granulosa cells by targeting ASB9.Journal of animal science and biotechnology · 2023Article
- The time dimension to stroke: Circadian effects on stroke outcomes and mechanisms.Neurochemistry international · 2023Article
- Circadian Genes Expression Patterns in Disorders Due to Enzyme Deficiencies in the Heme Biosynthetic Pathway.Biomedicines · 2022Article
- A Chemical Proteomic Map of Heme-Protein Interactions.Journal of the American Chemical Society · 2022Article
- Nutrients and the Circadian Clock: A Partnership Controlling Adipose Tissue Function and Health.Nutrients · 2022Review
- Molecular regulations of circadian rhythm and implications for physiology and diseases.Signal transduction and targeted therapy · 2022Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
13 authors at 4 institutions in 1 country.
Funding
Abstract
The circadian clock is an endogenous time-keeping system that is ubiquitous in animals and plants as well as some bacteria. In mammals, the clock regulates the sleep-wake cycle via 2 basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) domain proteins-CLOCK and BMAL1. There is emerging evidence to suggest that heme affects circadian control, through binding of heme to various circadian proteins, but the mechanisms of regulation are largely unknown. In this work we examine the interaction of heme with human CLOCK (hCLOCK). We present a crystal structure for the PAS-A domain of hCLOCK, and we examine heme binding to the PAS-A and PAS-B domains. UV-visible and electron paramagnetic resonance spectroscopies are consistent with a bis-histidine ligated heme species in solution in the oxidized (ferric) PAS-A protein, and by mutagenesis we identify His144 as a ligand to the heme. There is evidence for flexibility in the heme pocket, which may give rise to an additional Cys axial ligand at 20K (His/Cys coordination). Using DNA binding assays, we demonstrate that heme disrupts binding of CLOCK to its E-box DNA target. Evidence is presented for a conformationally mobile protein framework, which is linked to changes in heme ligation and which has the capacity to affect binding to the E-box. Within the hCLOCK structural framework, this would provide a mechanism for heme-dependent transcriptional regulation.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
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.