論文 - 詳細
| RRC ID | 53813 |
|---|---|
| 著者 | Shinohara Y, Koyama YM, Ukai-Tadenuma M, Hirokawa T, Kikuchi M, Yamada RG, Ukai H, Fujishima H, Umehara T, Tainaka K, Ueda HR. |
| タイトル | Temperature-Sensitive Substrate and Product Binding Underlie Temperature-Compensated Phosphorylation in the Clock. |
| ジャーナル | Mol Cell |
| Abstract |
Temperature compensation is a striking feature of the circadian clock. Here we investigate biochemical mechanisms underlying temperature-compensated, CKIδ-dependent multi-site phosphorylation in mammals. We identify two mechanisms for temperature-insensitive phosphorylation at higher temperature: lower substrate affinity to CKIδ-ATP complex and higher product affinity to CKIδ-ADP complex. Inhibitor screening of ADP-dependent phosphatase activity of CKIδ identified aurintricarboxylic acid (ATA) as a temperature-sensitive kinase activator. Docking simulation of ATA and mutagenesis experiment revealed K224D/K224E mutations in CKIδ that impaired product binding and temperature-compensated primed phosphorylation. Importantly, K224D mutation shortens behavioral circadian rhythms and changes the temperature dependency of SCN's circadian period. Interestingly, temperature-compensated phosphorylation was evolutionary conserved in yeast. Molecular dynamics simulation and X-ray crystallography demonstrate that an evolutionally conserved CKI-specific domain around K224 can provide a structural basis for temperature-sensitive substrate and product binding. Surprisingly, this domain can confer temperature compensation on a temperature-sensitive TTBK1. These findings suggest the temperature-sensitive substrate- and product-binding mechanisms underlie temperature compensation. |
| 巻・号 | 67(5) |
| ページ | 783-798.e20 |
| 公開日 | 2017-9-7 |
| DOI | 10.1016/j.molcel.2017.08.009 |
| PII | S1097-2765(17)30606-8 |
| PMID | 28886336 |
| MeSH | Adenosine Triphosphate / metabolism* Animals Binding Sites Casein Kinase Idelta / chemistry Casein Kinase Idelta / genetics Casein Kinase Idelta / metabolism* Catalytic Domain Circadian Clocks* Circadian Rhythm* Crystallography, X-Ray Genotype HEK293 Cells Humans Hydrolysis Kinetics Locomotion Mice, Transgenic Models, Biological Molecular Docking Simulation Molecular Dynamics Simulation Mutation Phenotype Phosphorylation Protein Binding Protein Domains Saccharomyces cerevisiae / enzymology Saccharomyces cerevisiae / genetics Serine Structure-Activity Relationship Substrate Specificity Suprachiasmatic Nucleus / enzymology* Temperature* Tissue Culture Techniques Transfection |
| IF | 15.584 |
| 引用数 | 26 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
|
| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 62 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 遺伝子材料 | pHisGST CKI delta (RDB15964) pHisGST CKI homolog 1 (RDB15965) |