The role of Asp578 in maintaining the inactive conformation of the human lutropin/choriogonadotropin receptor.

The Journal of Biological Chemistry
S KosugiA Shenker

Abstract

A constitutively activating mutation encoding Asp578-->Gly in transmembrane helix 6 of the lutropin/choriogonadotropin receptor (LHR) is the most common cause of gonadotropin-independent, male-limited precocious puberty. This mutant LHR produces a 4.5-fold increase in basal cAMP when expressed in COS-7 cells. To better understand the normal role of Asp578 in the LHR we studied the effect of seven other amino acid substitutions at this position. No agonist binding or response was detected with the Asp578-->Pro mutant. Agonist binding affinity was unaffected by the other substitutions and estimated receptor concentrations ranged from 11 to 184% of wild type. Substitution of Asp578 with Asn, a similarly sized, uncharged residue, did not produce agonist-independent activation. In contrast, replacement with Glu, Ser, or Leu caused 4. 9-5.6-fold stimulation of basal cAMP. Substitution with Tyr (8.5-fold) or Phe (7.5-fold) had a greater activating effect. Only the Tyr, Phe, and Leu mutants showed constitutive activation of the inositol phosphate pathway. Our data suggest that it is the ability of the Asp578 side chain to serve as a properly positioned hydrogen bond acceptor, rather than its negative charge, that is important for stabi...Continue Reading

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Citations

Jan 15, 1999·Pharmacology & Therapeutics·J Wess
Jul 20, 1999·Molecular and Cellular Endocrinology·T SchönebergT Gudermann
Apr 29, 1998·Annual Review of Physiology·M L Dufau
May 23, 2014·Journal of Assisted Reproduction and Genetics·Frederic MitriRobert F Casper
Sep 14, 2010·Cellular and Molecular Life Sciences : CMLS·Krassimira AngelovaFrancesca Fanelli
Oct 21, 2015·Frontiers in Endocrinology·Prema Narayan
Aug 12, 2004·The Journal of Biological Chemistry·William R MoyleMichael P Bernard
Feb 23, 2002·The Journal of Biological Chemistry·ChangWoo LeeTae H Ji
Apr 12, 2002·Endocrine Reviews·Mario AscoliDeborah L Segaloff
Jul 20, 2002·Endocrinology·Lisa M SalvadorMary Hunzicker-Dunn
Apr 15, 2000·Methods : a Companion to Methods in Enzymology·J GromollW Höppner

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