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Comparison of Wildtype vs. FASPS Mammalian Molecular Clocks. By Erin Eppler May 2010. http://www.soundlighthealer.com/images/circadian_clock_1.jpg. A Typical Circadian Rhythm. A circadian rhythm has a period of 24-25 hours, approximately one day’s length

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comparison of wildtype vs fasps mammalian molecular clocks

Comparison of Wildtype vs. FASPS Mammalian Molecular Clocks

By Erin Eppler

May 2010

http://www.soundlighthealer.com/images/circadian_clock_1.jpg

a typical circadian rhythm
A Typical Circadian Rhythm
  • A circadian rhythm has a period of 24-25 hours, approximately one day’s length
  • The master clock or suprachiasmatic nucleus (SCN) resides within the hypothalamus
  • When light strikes specialized ganglion cells of the eye, an electrical impulse is sent to the SCN, accelerating the transcription of Per and Cry genes by CLOCK-Baml1 dimers, whose concentrations increase during the subjective night
  • The cycle is a series of positive and negative feed back loops
legend
Legend
  • Baml1 gene
  • Baml1 protein
  • CLOCK gene
  • CLOCK protein
  • Per gene
  • PER protein
  • Cry gene
  • CRY protein
  • Ribosome
  • Phosphorylating
  • Unstable PER protein
  • CylinKinaseε

CKIε

slide4

Ribosomes

CKIε

During the subjective night concentrations of Baml1 and CLOCK proteins increase. Newly synthesized mRNA is

transported from the nucleus to the cytoplasm where it is transcribed into Baml1 and CLOCK proteins.

Baml1

CLOCK

Per 1

Per 2

Per 3

Cry 1

Cry 2

CKIε

Nucleus

CKIε

Cytoplasm

slide5

Ribosomes

CKIε

Baml1 and CLOCK protein dimerize and re-enter the nucleus where they bind to E-boxes on the promoter

region of Per and Cry genes, accelerating transcription.

Baml1

CLOCK

Per 1

Per 2

Per 3

Cry 1

Cry 2

CKIε

Nucleus

CKIε

Cytoplasm

slide6

Cytoplasm

CKIε

Movement of proteins out of the nucleus and into the cytoplasm

Baml1

Ribosomes

CLOCK

CKIε

Per 1

Per 2

Per 3

CKIε

Cry 1

Cry 2

Nucleus

slide7

Cytoplasm

CKIε

PER proteins that do not form a dimer are susceptible to phosphorylation by CKIε (CyclinKinaseε) making

them less stable, leading to their degradation.

Baml1

Ribosomes

CLOCK

CKIε

Phosphorylation

Per 1

Per 2

Per 3

CKIε

Cry 1

Cry 2

Nucleus

slide8

Unstablization of PER proteins

Cytoplasm

CKIε

Baml1

Ribosomes

CLOCK

CKIε

Per 1

Per 2

Per 3

CKIε

Cry 1

Cry 2

Nucleus

slide9

Cytoplasm

CKIε

CRY-PER or PER-PER dimers form in the cytoplasm and transport back into the nucleus. A CRY-PER dimer

binds Baml1 and Cry genes, blocking transcription which leads to a negative feedback loop.

Baml1

Ribosomes

CLOCK

Per 1

Per 2

Per 3

CKIε

Cry 1

Cry 2

Nucleus

CKIε

slide10

Cytoplasm

CKIε

Baml1 and CLOCK protein concentrations decrease over time.

Baml1

Ribosomes

CLOCK

Per 1

Per 2

Per 3

CKIε

Cry 1

Cry 2

Nucleus

CKIε

slide11

Cytoplasm

CKIε

Degradation of BAM and CLOCK proteins will eventually prevent transcription of Per and Cry genes

Baml1

Ribosomes

CLOCK

CKIε

Per 1

Per 2

Per 3

CKIε

Cry 1

Cry 2

Nucleus

slide12

Cytoplasm

CKIε

Baml1

Ribosomes

CLOCK

CKIε

Per 1

Per 2

Per 3

CKIε

Cry 1

Cry 2

Nucleus

slide13

Cytoplasm

CKIε

PER and CRY concentrations decrease and unblock Baml1 and CLOCK genes, thus restarting the cycle.

Baml1

Ribosomes

CLOCK

CKIε

Per 1

Per 2

Per 3

CKIε

Cry 1

Cry 2

Nucleus

familial sleep phase syndrome fasps molecular clock
Familial Sleep Phase Syndrome (FASPS) Molecular Clock
  • Mutation occurs in the PER2 gene
  • Circadian rhythm is advanced by 4-5 hours
slide15

CKIε

The FASPS mutation causes accelerated nuclear clearance of PER2, but complex formation with

CRY1 prevents nuclear export thereby causing nuclear accumulation and protein stabilization

Baml1

Ribosomes

CLOCK

Per 1

Per 2

Per 3

CKIε

Cry 1

Cry 2

Nucleus

CKIε

Cytoplasm