HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Accepted manuscript (PDF) Supplementary Data All Versions of this Article: JME-08-0040v1 41/3/145    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nunez Miguel, R. Articles by Rees Smith, B. Search for Related Content PubMed PubMed Citation Articles by Nunez Miguel, R. Articles by Rees Smith, B.

R Nunez Miguel, FIRS Laboratories, RSR Ltd, Cardiff, United Kingdom
J Sanders, FIRS Laboratories, RSR Ltd, Cardiff, United Kingdom
D Chirgadze, Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
T Blundell, Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
J Furmaniak, FIRS Laboratories, RSR Ltd, Cardiff , United Kingdom
B Rees Smith, FIRS Laboratories, RSR Ltd, Cardiff, United Kingdom

Correspondence: Jadwiga Furmaniak, Email: firs{at}rsrltd.eclipse.co.uk

Abstract

The crystal structures of the leucine-rich repeat domain (LRD) of the follicle stimulating hormone (FSH) receptor (FSHR) in complex with FSH and the thyroid stimulating hormone (TSH) receptor (TSHR) LRD in complex with the thyroid stimulating autoantibody (M22) provide opportunities to assess the molecular basis of the specificity of glycoprotein hormone-receptor binding. A comparative model of the TSH-TSHR complex was built using the two solved crystal structures and verified using studies on receptor affinity and activation. Analysis of the FSH-FSHR and TSH-TSHR complexes allowed identification of receptor residues that may be important in hormone binding specificity. These residues are in leucine rich repeats at the two ends of the FSHR and the TSHR LRD structures but not in their central repeats. Interactions in the interfaces are consistent with a higher FSH binding affinity for the FSHR compared to the binding affinity of TSH for the TSHR. The higher binding affinity of porcine (p)TSH and bovine (b)TSH for human (h)TSHR compared to hTSH appears not to be dependent on interactions with the TSHR LRD as none of the residues that differ among hTSH, pTSH or bTSH interact with the LRD. This suggests that thyroid stimulating hormones are likely to interact with other parts of the receptors in addition to the LRD with these non-LRD interactions being responsible for affinity differences. Analysis of interactions in the FSH-FSHR and TSH-TSHR complexes suggests that the chains of both hormones tend to be involved in the receptor activation process while the β chains are more involved in defining binding specificity.

This article has been cited by other articles:

				R Nunez Miguel, J Sanders, D Y Chirgadze, J Furmaniak, and B Rees Smith Thyroid stimulating autoantibody M22 mimics TSH binding to the TSH receptor leucine rich domain: a comparative structural study of protein-protein interactions J. Mol. Endocrinol., May 1, 2009; 42(5): 381 - 395. [Abstract] [Full Text] [PDF]