|
|
|
|||||||
|
|||||||||
(Received for publication, August 6, 1996, and in revised form, September 20, 1996)
From the ¶ Department of Laboratory Medicine, Kyoto
University School of Medicine, Kyoto 606-01, Japan,
" Metabolic Diseases Branch, NIDDK, National Institutes of Health,
Bethesda, Maryland 20892, and A constitutively activating mutation encoding
Asp578
Volume 271, Number 50,
Issue of December 13, 1996
pp. 31813-31817
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
Division of Endocrinology,
Department of Pediatrics, Northwestern University Medical School
and Children's Memorial Hospital, Chicago, Illinois 60614
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
Asp578Pro 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 stabilizing the inactive state
of the LHR. A bulky aromatic side chain at position 578 may further
destabilize the inactive receptor conformation.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  P. Nurwakagari, A. Breit, C. Hess, H. Salman-Livny, D. Ben-Menahem, and T. Gudermann A conformational contribution of the luteinizing hormone-receptor ectodomain to receptor activation J. Mol. Endocrinol., February 1, 2007; 38(2): 259 - 275. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Ringkananont, J. Van Durme, L. Montanelli, F. Ugrasbul, Y. M. Yu, R. E. Weiss, S. Refetoff, and H. Grasberger Repulsive Separation of the Cytoplasmic Ends of Transmembrane Helices 3 and 6 Is Linked to Receptor Activation in a Novel Thyrotropin Receptor Mutant (M626I) Mol. Endocrinol., April 1, 2006; 20(4): 893 - 903. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Soriano-Guillen, N. Lahlou, G. Chauvet, M. Roger, J. L. Chaussain, and J. C. Carel Adult Height after Ketoconazole Treatment in Patients with Familial Male-Limited Precocious Puberty J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 147 - 151. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. R. Moyle, Y. Xing, W. Lin, D. Cao, R. V. Myers, J. E. Kerrigan, and M. P. Bernard Model of Glycoprotein Hormone Receptor Ligand Binding and Signaling J. Biol. Chem., October 22, 2004; 279(43): 44442 - 44459. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hirakawa and M. Ascoli A Constitutively Active Somatic Mutation of the Human Lutropin Receptor Found in Leydig Cell Tumors Activates the Same Families of G Proteins as Germ Line Mutations Associated with Leydig Cell Hyperplasia Endocrinology, September 1, 2003; 144(9): 3872 - 3878. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Angelova, F. Fanelli, and D. Puett A Model for Constitutive Lutropin Receptor Activation Based on Molecular Simulation and Engineered Mutations in Transmembrane Helices 6 and 7 J. Biol. Chem., August 23, 2002; 277(35): 32202 - 32213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Salvador, E. Maizels, D. B. Hales, E. Miyamoto, H. Yamamoto, and M. Hunzicker-Dunn Acute Signaling by the LH Receptor Is Independent of Protein Kinase C Activation Endocrinology, August 1, 2002; 143(8): 2986 - 2994. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. Berlot A Highly Effective Dominant Negative alpha s Construct Containing Mutations That Affect Distinct Functions Inhibits Multiple Gs-coupled Receptor Signaling Pathways J. Biol. Chem., May 31, 2002; 277(23): 21080 - 21085. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Lee, I. Ji, K. Ryu, Y. Song, P. M. Conn, and T. H. Ji Two Defective Heterozygous Luteinizing Hormone Receptors Can Rescue Hormone Action J. Biol. Chem., May 3, 2002; 277(18): 15795 - 15800. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ascoli, F. Fanelli, and D. L. Segaloff The Lutropin/Choriogonadotropin Receptor, A 2002 Perspective Endocr. Rev., April 1, 2002; 23(2): 141 - 174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hirakawa, C. Galet, and M. Ascoli MA-10 Cells Transfected with the Human Lutropin/Choriogonadotropin Receptor (hLHR): A Novel Experimental Paradigm to Study the Functional Properties of the hLHR Endocrinology, March 1, 2002; 143(3): 1026 - 1035. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Neumann, G. Krause, S. Chey, and R. Paschke A Free Carboxylate Oxygen in the Side Chain of Position 674 in Transmembrane Domain 7 Is Necessary for TSH Receptor Activation Mol. Endocrinol., August 1, 2001; 15(8): 1294 - 1305. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Min and M. Ascoli Effect of Activating and Inactivating Mutations on the Phosphorylation and Trafficking of the Human Lutropin/Choriogonadotropin Receptor Mol. Endocrinol., November 1, 2000; 14(11): 1797 - 1810. [Abstract] [Full Text]
|
|
|
|
|
|
S. Nishi, S. Y. Hsu, K. Zell, and A. J. W. Hsueh Characterization of Two Fly LGR (Leucine-Rich Repeat-Containing, G Protein-Coupled Receptor) Proteins Homologous to Vertebrate Glycoprotein Hormone Receptors: Constitutive Activation of Wild-Type Fly LGR1 But Not LGR2 in Transfected Mammalian Cells Endocrinology, November 1, 2000; 141(11): 4081 - 4090. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. N. Themmen and I. T. Huhtaniemi Mutations of Gonadotropins and Gonadotropin Receptors: Elucidating the Physiology and Pathophysiology of Pituitary-Gonadal Function Endocr. Rev., October 1, 2000; 21(5): 551 - 583. [Abstract] [Full Text]
|
|
|
|
|
|
S. Y. Hsu, M. Kudo, T. Chen, K. Nakabayashi, A. Bhalla, P. J. van der Spek, M. van Duin, and A. J. W. Hsueh The Three Subfamilies of Leucine-Rich Repeat-Containing G Protein-Coupled Receptors (LGR): Identification of LGR6 and LGR7 and the Signaling Mechanism for LGR7 Mol. Endocrinol., August 1, 2000; 14(8): 1257 - 1271. [Abstract] [Full Text]
|
|
|
|
|
|
Y.-X. Tao, A. N. Abell, X. Liu, K. Nakamura, and D. L. Segaloff Constitutive Activation of G Protein-Coupled Receptors as a Result of Selective Substitution of a Conserved Leucine Residue in Transmembrane Helix III Mol. Endocrinol., August 1, 2000; 14(8): 1272 - 1282. [Abstract] [Full Text]
|
|
|
|
 |
|
 G. Liu, L. Duranteau, J.-C. Carel, J. Monroe, D. A. Doyle, and A. Shenker Leydig-Cell Tumors Caused by an Activating Mutation of the Gene Encoding the Luteinizing Hormone Receptor N. Engl. J. Med., December 2, 1999; 341(23): 1731 - 1736. [Full Text] [PDF]
|
|
|
|
|
|
K. Nakamura, M. d. F. M. Lazari, S. Li, C. Korgaonkar, and M. Ascoli Role of the Rate of Internalization of the Agonist-Receptor Complex on the Agonist-Induced Down-Regulation of the Lutropin/ Choriogonadotropin Receptor Mol. Endocrinol., August 1, 1999; 13(8): 1295 - 1304. [Abstract] [Full Text]
|
|
|
|
|
|
S. Mukherjee, K. Palczewski, V. V. Gurevich, and M. Hunzicker-Dunn beta -Arrestin-dependent Desensitization of Luteinizing Hormone/Choriogonadotropin Receptor Is Prevented by a Synthetic Peptide Corresponding to the Third Intracellular Loop of the Receptor J. Biol. Chem., May 7, 1999; 274(19): 12984 - 12989. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Rajagopalan-Gupta, S. Mukherjee, X. Zhu, Y.-K. Ho, H. Hamm, M. Birnbaumer, L. Birnbaumer, and M. Hunzicker-Dunn Roles of Gi and Gq/11 in Mediating Desensitization of the Luteinizing Hormone/Choriogonadotropin Receptor in Porcine Ovarian Follicular Membranes Endocrinology, April 1, 1999; 140(4): 1612 - 1621. [Abstract] [Full Text]
|
|
|
|
|
|
K.-S. Min, X. Liu, J. Fabritz, J. Jaquette, A. N. Abell, and M. Ascoli Mutations That Induce Constitutive Activation and Mutations That Impair Signal Transduction Modulate the Basal and/or Agonist-stimulated Internalization of the Lutropin/Choriogonadotropin Receptor J. Biol. Chem., December 25, 1998; 273(52): 34911 - 34919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. N. Abell, D. J. McCormick, and D. L. Segaloff Certain Activating Mutations within Helix 6 of the Human Luteinizing Hormone Receptor May Be Explained by Alterations That Allow Transmembrane Regions to Activate Gs Mol. Endocrinol., December 1, 1998; 12(12): 1857 - 1869. [Abstract] [Full Text]
|
|
|
|
|
|
R. M. Rajagopalan-Gupta, M. L. G. Lamm, S. Mukherjee, M. M. Rasenick, and M. Hunzicker-Dunn Luteinizing Hormone/Choriogonadotropin Receptor-Mediated Activation of Heterotrimeric Guanine Nucleotide Binding Proteins in Ovarian Follicular Membranes Endocrinology, November 1, 1998; 139(11): 4547 - 4555. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Pawate, K. L. Schey, G. P. Meier, M. E. Ullian, D. E. Mais, and P. V. Halushka Expression, Characterization, and Purification of C-terminally Hexahistidine-tagged Thromboxane A2 Receptors J. Biol. Chem., August 28, 1998; 273(35): 22753 - 22760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. C. Ganguli, C.-G. Park, M. H. Holtmann, E. M. Hadac, T. P. Kenakin, and L. J. Miller Protean Effects of a Natural Peptide Agonist of the G Protein-Coupled Secretin Receptor Demonstrated by Receptor Mutagenesis J. Pharmacol. Exp. Ther., August 1, 1998; 286(2): 593 - 598. [Abstract] [Full Text]
|
|
|
|
 |
|
 S. Kosugi, T. Mori, and A. Shenker An Anionic Residue at Position 564 Is Important for Maintaining the Inactive Conformation of the Human Lutropin/Choriogonadotropin Receptor Mol. Pharmacol., May 1, 1998; 53(5): 894 - 901. [Abstract] [Full Text]
|
|
|
|
|
|
K. Nakabayashi, M. Kudo, B. Kobilka, and A. J. W. Hsueh Activation of the Luteinizing Hormone Receptor Following Substitution of Ser-277 with Selective Hydrophobic Residues in the Ectodomain Hinge Region J. Biol. Chem., September 22, 2000; 275(39): 30264 - 30271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Schulz, K. Bruns, P. Henklein, G. Krause, M. Schubert, T. Gudermann, V. Wray, G. Schultz, and T. Schoneberg Requirement of Specific Intrahelical Interactions for Stabilizing the Inactive Conformation of Glycoprotein Hormone Receptors J. Biol. Chem., November 22, 2000; 275(48): 37860 - 37869. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Govaerts, A. Lefort, S. Costagliola, S. J. Wodak, J. A. Ballesteros, J. Van Sande, L. Pardo, and G. Vassart A Conserved Asn in Transmembrane Helix 7 Is an On/Off Switch in the Activation of the Thyrotropin Receptor J. Biol. Chem., June 15, 2001; 276(25): 22991 - 22999. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |