205. Circadian Clock Molecular

Circadian Clock Molecular

This simulation models the mammalian circadian clock, a molecular oscillator that generates ~24-hour rhythms in gene expression, physiology, and behavior.

Core Transcription-Translation Feedback Loop (TTFL)

• Positive Limb: CLOCK:BMAL1 heterodimer binds E-box sequences, activating Per and Cry gene transcription
• Negative Limb: PER and CRY proteins accumulate, enter nucleus, and inhibit CLOCK:BMAL1
• Delay: Post-translational modifications create the ~24h period

Dual Repression Mechanisms

• Blocking (CRY alone): CRY binds CLOCK:BMAL1 on DNA, blocking transcription without displacement
• Displacement (PER+CRY): PER enables CK1-mediated phosphorylation that removes CLOCK:BMAL1 from E-boxes

Post-Translational Regulation

• CK1ε/δ: Phosphorylates PER proteins, promoting ubiquitination and degradation
• AMPK: Phosphorylates CRY proteins for degradation
• SCF E3 ligases: βTrCP and FBXL3 target phosphorylated PER and CRY

Additional Feedback Loops

• REV-ERBα: Represses Bmal1 transcription (stabilizing loop)
• RORα: Activates Bmal1 transcription
• PER2: Positive regulator of Bmal1 expression

Circadian Phases

• Day (Activation): CLOCK:BMAL1 active, Per/Cry genes transcribed
• Evening (Repression): PER:CRY complex accumulates, inhibits CLOCK:BMAL1
• Night (Repressed): Minimal transcription, proteins degrading
• Dawn (Recovery): PER/CRY cleared, CLOCK:BMAL1 reactivates