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Molecular and structural effects of inverse agonistic mutations on signaling of the thyrotropin receptor--a basally

G Kleinau1, H Jaeschke, S Mueller

  • 1Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.

Cellular and Molecular Life Sciences : CMLS
|October 14, 2008
PubMed

Insights

Mutations reducing G-protein coupled receptor (GPCR) signaling impair both basal and activated states. Silencing a GPCR’s basal activity may reduce its overall signaling capacity, impacting disease mechanisms.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • G-protein coupled receptors (GPCRs) exhibit basal signaling activity, and mutations can decrease this, leading to pathogenic implications.
  • Understanding the interplay between basal and activated receptor conformations is crucial for deciphering GPCR function.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying decreased basal signaling activity in GPCRs.
  • To explore the relationship between basal and activated receptor conformations.
  • To characterize the impact of mutations on thyroid stimulating hormone receptor (TSHR) signaling.

Main Methods:

  • Creation of double mutations in the TSHR with opposing effects on basal activity.
  • Characterization of basal and TSH-induced signaling in mutant TSHR forms.
  • Development of TSHR models based on rhodopsin and opsin crystal structures.

Main Results:

  • Mutations that lower basal activity of TSHR also suppress TSH-induced signaling and constitutively activating mutations (CAMs).
  • A conformationally 'silenced' GPCR exhibits reduced intrinsic signaling capacity compared to wild-type.
  • Distinct conformational and intramolecular interactions were observed between inactive and partially active TSHR models.

Conclusions:

  • Decreased basal GPCR activity is linked to impaired signaling in both basal and activated states.
  • The conformational state of a GPCR significantly influences its signaling potential.
  • Structural modeling provides insights into the molecular basis of mutations affecting GPCR basal activity.

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