From molecular details of the interplay between transmembrane helices of the thyrotropin receptor to general aspects of signal transduction in family a G-protein-coupled receptors (GPCRs)

Item Type:	Article
Title:	From molecular details of the interplay between transmembrane helices of the thyrotropin receptor to general aspects of signal transduction in family a G-protein-coupled receptors (GPCRs)
Creators Name:	Kleinau, G. and Hoyer, I. and Kreuchwig, A. and Haas, A.K. and Rutz, C. and Furkert, J. and Worth, C.L. and Krause, G. and Schülein, R.
Abstract:	Transmembrane helices (TMHs) 5 and 6 are known to be important for signal transduction by G-protein-coupled receptors (GPCRs). Our aim was to characterize the interface between TMH5 and TMH6 of the thyrotropin receptor (TSHR) to gain molecular insights into aspects of signal transduction and regulation. A proline at TMH5 position 5.50 is highly conserved in family A GPCRs and causes a twist in the helix structure. Mutation of the TSHR-specific alanine (Ala-593⁵·⁵⁰) at this position to proline resulted in a 20-fold reduction of cell surface expression. This indicates that TMH5 in the TSHR might have a conformation different from most other family A GPCRs by forming a regular α-helix. Furthermore, linking our own and previous data from directed mutagenesis with structural information led to suggestions of distinct pairs of interacting residues between TMH5 and TMH6 that are responsible for stabilizing either the basal or the active state. Our insights suggest that the inactive state conformation is constrained by a core set of polar interactions among TMHs 2, 3, 6, and 7 and in contrast that the active state conformation is stabilized mainly by non-polar interactions between TMHs 5 and 6. Our findings might be relevant for all family A GPCRs as supported by a statistical analysis of residue properties between the TMHs of a vast number of GPCR sequences.
Keywords:	G-Protein-Coupled Receptors (GPCR), Receptor Structure-Function, Receptors, Signal Transduction, Thyroid, Animals
Source:	Journal of Biological Chemistry
ISSN:	0021-9258
Publisher:	American Society for Biochemistry and Molecular Biology
Volume:	286
Number:	29
Page Range:	25859-25871
Date:	22 July 2011
Official Publication:	https://doi.org/10.1074/jbc.M110.196980
PubMed:	View item in PubMed

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