Understanding the design principle of circadian oscillator in mammals through reconstitution

2017 Fiscal Year Final Research Report

• Project/Area Number: 25221004
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: System genome science
• Research Institution: The University of Tokyo
• Principal Investigator: Ueda Hiroki 東京大学, 大学院医学系研究科(医学部), 教授 (20373277)
• Co-Investigator(Kenkyū-buntansha): 洲崎 悦生 東京大学, 大学院医学系研究科(医学部), 講師 (10444803) ; 大出 晃士 東京大学, 大学院医学系研究科(医学部), 助教 (40612122) ; 田井中 一貴 東京大学, 大学院医学系研究科(医学部), 講師 (80506113)
• Project Period (FY): 2013-05-31 – 2018-03-31
• Keywords: 合成生物学 / リン酸化 / 概日時計 / 温度補償性 / 遺伝子改変マウス

Outline of Final Research Achievements

The aim of this study is to understand the molecular mechanisms driving the temperature-compensated mammalian circadian clock through reconstitution. CKIδ determines the period of mammalian circadian clocks and its kinase activity is almost unchanged under physiological temperature range. We found that the temperature compensation is achieved through 1) decreased kinase-substrate affinity and 2) elevated affinity between the kinase and a phosphorylated product. We further identified the responsible domain of CKIδ for the temperature-dependent product binding. The domain can confer temperature compensation on the otherwise temperature-sensitive kinase. Behavioral circadian period as well as temperature sensitivity of circadian period of SCN was significantly altered in the genetically modified mice having the mutant CKIδ. In summary, we uncovered the molecular mechanism underlying the temperature-compensation of CKIδaction in vitro, and partly its physiological significance in vivo.

Free Research Field

システム生物学