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Article
Intrinsic differences in the response of the human lutropin receptor versus the human follitropin receptor to activating mutations
The Journal of biological chemistry
  • Meilin Zhang, University of Iowa
  • Ya-Xiong Tao, University of Iowa
  • Ginny L. Ryan, University of Iowa
  • Xiuyan Feng, University of Iowa
  • Francesca Fanelli, University of Modena e Reggio Emilia
  • Deborah L. Segaloff, University of Iowa
Document Type
Article
Peer Reviewed
1
Publication Date
8-31-2007
NLM Title Abbreviation
J Biol Chem
PubMed ID
17609213
DOI of Published Version
10.1074/jbc.M703500200
Abstract
In contrast to the human lutropin receptor (hLHR), very few naturally occurring activating mutations of the structurally related human follitropin receptor (hFSHR) have been identified. The present study was undertaken to determine if one aspect underlying this discrepancy might be a general resistance of the hFSHR to mutation-induced constitutive activity. Five different mutations were introduced into both the hLHR and hFSHR (four based on activating mutations of the hLHR gene, one based on an activating mutation of the hFSHR gene). Our results demonstrate that hFSHR constitutively activating mutants (CAMs) were not as active as hLHR CAMs containing the comparable mutation. Furthermore, although all hFSHR CAMs exhibited strong promiscuous activation by high concentrations of the other glycoprotein hormone receptors, hLHR CAMs showed little or no promiscuous activation. Our in vitro findings are consistent with in vivo observations of known pathophysiological conditions associated with hLHR CAMs, but not hFSHR CAMs, and with promiscuous activation of hFSHR CAMs, but not hLHR CAMs. Computational experiments suggest that the mechanisms through which homologous mutations increase the basal activity of the hLHR and the hFSHR are similar. This is particularly true for the strongest CAMs like L460(3.43)R. Disparate properties of the hLHR versus hFSHR CAMs may, therefore, be due to differences in shape and electrostatics features of the solvent-exposed cytosolic receptor domains involved in the receptor-G protein interface rather than to differences in the nature of local perturbation at the mutation site or in the way local perturbation is transferred to the putative G protein binding domains.
Keywords
  • Cell Line,
  • Child,
  • Child,
  • Preschool,
  • GTP-Binding Proteins/genetics/metabolism,
  • Humans,
  • Male,
  • Protein Binding/genetics,
  • Protein Structure,
  • Tertiary/genetics,
  • Puberty,
  • Precocious/genetics/metabolism,
  • Receptors,
  • FSH/genetics/metabolism,
  • Receptors,
  • LH/genetics/metabolism,
  • Static Electricity
Published Article/Book Citation

The Journal of biological chemistry, 282:35 (2007) pp.25527-25539.

Citation Information
Meilin Zhang, Ya-Xiong Tao, Ginny L. Ryan, Xiuyan Feng, et al.. "Intrinsic differences in the response of the human lutropin receptor versus the human follitropin receptor to activating mutations" The Journal of biological chemistry Vol. 282 Iss. 35 (2007) p. 25527 - 25539 ISSN: 0021-9258
Available at: http://works.bepress.com/ginny_ryan/20/