Dynamics at the serine loop underlie differential affinity of cryptochromes for CLOCK:BMAL1 to control circadian timing.

Autor:	Fribourgh JL; Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, United States., Srivastava A; Institute of Transformative Bio-Molecules, Nagoya University, Nagoya, Japan., Sandate CR; The Scripps Research Institute, La Jolla, United States., Michael AK; Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, United States., Hsu PL; Department of Pharmacology, University of Washington, Seattle, United States., Rakers C; Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan., Nguyen LT; Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, United States., Torgrimson MR; Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, United States., Parico GCG; Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, United States., Tripathi S; Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, United States., Zheng N; Department of Pharmacology, University of Washington, Seattle, United States.; Howard Hughes Medical Institute, Seattle, United States., Lander GC; The Scripps Research Institute, La Jolla, United States., Hirota T; Institute of Transformative Bio-Molecules, Nagoya University, Nagoya, Japan., Tama F; Institute of Transformative Bio-Molecules, Nagoya University, Nagoya, Japan.; Department of Physics, Nagoya University, Nagoya, Japan.; RIKEN Center for Computational Science, Kobe, Japan., Partch CL; Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, United States.; Center for Circadian Biology, University of California San Diego, La Jolla, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2020 Feb 26; Vol. 9. Date of Electronic Publication: 2020 Feb 26.
DOI:	10.7554/eLife.55275
Abstrakt:	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. Competing Interests: JF, AS, CS, AM, PH, CR, LN, MT, GP, ST, NZ, GL, TH, FT, CP No competing interests declared (© 2020, Fribourgh et al.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu