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

Item Type:Article
Title:Molecular and structural effects of inverse agonistic mutations on signaling of the thyrotropin receptor - a basally active GPCR
Creators Name:Kleinau, G. and Jaeschke, H. and Mueller, S. and Worth, C.L. and Paschke, R. and Krause, G.
Abstract:Several mutations that decrease the basal signaling activity of G-protein coupled receptors (GPCRs) with pathogenic implications are known. Here we study the molecular mechanisms responsible for this phenotype and investigate how basal and further activated receptor conformations are interrelated. In the basally active thyroid stimulating hormone receptor (TSHR) we combined spatially-distant mutations with opposing effects on basal activity in double-mutations and characterized mutant basal and TSH induced signaling. Mutations lowering basal activity always have a suppressive influence on TSH induced signaling and on constitutively activating mutations (CAMs). Our results suggest that the conformation of a basally 'silenced' GPCR might impair its intrinsic capacity for signaling compared to the wild-type. Striking differences in conformation and intramolecular interactions between TSHR models built using the crystal structures of inactive rhodopsin and partially active opsin help illuminate the molecular details underlying mutations decreasing basal activity.
Keywords:Inverse Agonism, Signal Transduction, Activation Mechanism, endocrinology, Glycoprotein Hormone Receptors, TSHR, LHR, LHCGR, FSHR
Source:Cellular and Molecular Life Sciences
ISSN:1420-682X
Publisher:Springer (Switzerland)
Volume:65
Number:22
Page Range:3664-3676
Date:November 2008
Official Publication:https://doi.org/10.1007/s00018-008-8450-2
PubMed:View item in PubMed

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