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How serpins transport hormones and regulate their release.

Robin W Carrell1, Randy J Read1

  • 1Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.

Seminars in Cell & Developmental Biology
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PubMed
Summary

Hormone carriers like TBG and CBG use adaptable serpin structures for hormone release, functioning like protein thermocouples sensitive to temperature changes. Angiotensinogen, however, uses a unique extension for blood pressure regulation, not the serpin mechanism.

Keywords:
AngiotensinAngiotensinogenCBGCortisolTBGThyroxine

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Physiology

Background:

  • The serpin framework is adapted for diverse functions, including hormone transport.
  • Thyroxine and corticosteroids bind to thyroxine-binding globulin (TBG) and corticosteroid-binding globulin (CBG) at similar sites.
  • Previous understanding suggested fixed binding affinities for these carriers.

Purpose of the Study:

  • To investigate the mechanism of hormone release from TBG and CBG.
  • To explore the allosteric modification of binding affinities.
  • To compare the regulation of hormone carriers with angiotensinogen's role in blood pressure control.

Main Methods:

  • Analysis of recent structural findings on TBG and CBG.
  • Examination of hormone release dynamics based on temperature.
  • Comparison of serpin mechanism utilization versus alternative regulatory strategies.

Main Results:

  • Hormone release from TBG and CBG is equilibrated, not on-and-off, due to reversible hinge movements.
  • Binding affinities are allosterically modifiable, allowing differential hormone delivery.
  • TBG and CBG act as protein thermocouples, altering hormone release with temperature fluctuations.
  • Angiotensinogen utilizes a terminal extension for renin interaction, bypassing the serpin mechanism.
  • Redox status of a disulfide bridge in angiotensinogen is linked to blood pressure regulation, particularly in pre-eclampsia.

Conclusions:

  • The serpin framework's adaptability extends to dynamic hormone transport regulation.
  • TBG and CBG exhibit temperature-sensitive hormone release, impacting physiological states.
  • Angiotensinogen's unique structure offers a novel regulatory pathway for blood pressure control.
  • Disulfide bridge redox status represents a new regulatory level in blood pressure management.