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Isoform-selective regulation of mammalian cryptochromes

Simon Miller1, You Lee Son2, Yoshiki Aikawa1

  • 1Institute of Transformative Bio-Molecules, Nagoya University, Nagoya, Japan.

Nature Chemical Biology
|April 2, 2020
PubMed

Insights

New compounds KL101 and TH301 selectively stabilize CRY1 and CRY2, respectively. This research reveals their distinct roles in circadian rhythms and brown fat differentiation, impacting energy expenditure.

Area of Science:

  • Chronobiology
  • Molecular Biology
  • Metabolism

Background:

  • Cryptochromes (CRY1 and CRY2) are key circadian clock components regulating daily rhythms.
  • Evidence suggests distinct and overlapping functions between CRY1 and CRY2.
  • Targeting individual isoforms is crucial for understanding their specific roles.

Purpose of the Study:

  • To develop isoform-selective compounds for CRY1 and CRY2.
  • To elucidate the molecular mechanisms of compound selectivity.
  • To investigate the role of CRY1 and CRY2 in brown adipocyte differentiation and energy expenditure.

Main Methods:

  • Phenotypic screening of circadian clock modulators.
  • Identification and characterization of selective CRY1 (KL101) and CRY2 (TH301) stabilizers.
  • X-ray crystallography of CRY-compound complexes.
  • Assessment of brown adipocyte differentiation and energy expenditure.

Main Results:

  • KL101 and TH301 were identified as selective stabilizers for CRY1 and CRY2, respectively.
  • Crystal structures revealed conserved binding sites but differential selectivity mechanisms involving the C-terminal region.
  • CRY1 and CRY2 were found to enhance brown adipocyte differentiation.
  • These findings link CRY function to energy expenditure regulation.

Conclusions:

  • Isoform-selective CRY modulators provide powerful tools to dissect circadian clock component functions.
  • A unique mechanism involving the disordered C-terminal region dictates CRY1/CRY2 selectivity.
  • CRY1 and CRY2 play a novel role in brown adipogenesis and energy expenditure, mediated by specific isoform stabilization.

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