| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
(Received for publication, July 16, 1997, and in revised form, August 27, 1997)
From the Department of Medicine and Children's Service, Endocrine
Unit, Massachusetts General Hospital and Harvard Medical School,
Boston, Massachusetts 02114
The parathyroid hormone (PTH)-2 receptor
displays strong ligand selectivity in that it responds fully to PTH but
not at all to PTH-related peptide (PTHrP). In contrast, the PTH-1
receptor (PTH/PTHrP receptor) responds fully to both ligands.
Previously it was shown that two divergent residues in PTH and PTHrP
account for PTH-2 receptor selectivity; position 23 (Trp in PTH and Phe in PTHrP) determines binding selectivity and position 5 (Ile in PTH and
His in PTHrP) determines signaling selectivity. To identify sites in
the PTH-2 receptor involved in discriminating between His5 and Ile5, we constructed PTH-2
receptor/PTH-1 receptor chimeras, expressed them in COS-7 cells, and
tested for cAMP responsiveness to
[Trp23] PTHrP-(1-36), and to the nondiscriminating
peptide [Ile5,Trp23]PTHrP-(1-36) (the
Phe23
Volume 272, Number 46,
Issue of November 14, 1997
pp. 28861-28868
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
Residues in the Membrane-spanning and Extracellular Loop Regions
of the Parathyroid Hormone (PTH)-2 Receptor Determine Signaling
Selectivity for PTH and PTH-related Peptide
Trp modification enabled high affinity binding of
each ligand to the PTH-2 receptor). The chimeras revealed that the
membrane-spanning/loop region of the receptor determined
His5/Ile5 signaling selectivity. Subsequent
analysis of smaller cassette substitutions and then individual point
mutations led to the identification of two single residues that
function as major determinants of residue 5 signaling selectivity.
These residues, Ile244 at the extracellular end of
transmembrane helix 3, and Tyr318 at the COOH-terminal
portion of extracellular loop 2, are replaced by Leu and Ile in the
PTH-1 receptor, respectively. The results thus indicate a functional
interaction between two residues in the core region of the PTH-2
receptor and residue 5 of the ligand.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  R. Mann, M. J. Wigglesworth, and D. Donnelly Ligand-Receptor Interactions at the Parathyroid Hormone Receptors: Subtype Binding Selectivity Is Mediated via an Interaction between Residue 23 on the Ligand and Residue 41 on the Receptor Mol. Pharmacol., September 1, 2008; 74(3): 605 - 613. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Ross, P. Engel, Y. Abdallah, W. Kummer, and K. D. Schluter Tuberoinfundibular Peptide of 39 Residues: A New Mediator of Cardiac Function via Nitric Oxide Production in the Rat Heart Endocrinology, May 1, 2005; 146(5): 2221 - 2228. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Papasani, R. C. Gensure, Y.-L. Yan, Y. Gunes, J. H. Postlethwait, B. Ponugoti, M. R. John, H. Juppner, and D. A. Rubin Identification and Characterization of the Zebrafish and Fugu Genes Encoding Tuberoinfundibular Peptide 39 Endocrinology, November 1, 2004; 145(11): 5294 - 5304. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Gensure, B. Ponugoti, Y. Gunes, M. R. Papasani, B. Lanske, M. Bastepe, D. A. Rubin, and H. Juppner Identification and Characterization of Two Parathyroid Hormone-Like Molecules in Zebrafish Endocrinology, April 1, 2004; 145(4): 1634 - 1639. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Dong, Z. Li, M. Zang, D. I. Pinon, T. P. Lybrand, and L. J. Miller Spatial Approximation between Two Residues in the Mid-region of Secretin and the Amino Terminus of Its Receptor: INCORPORATION OF SEVEN SETS OF SUCH CONSTRAINTS INTO A THREE-DIMENSIONAL MODEL OF THE AGONIST-BOUND SECRETIN RECEPTOR J. Biol. Chem., November 28, 2003; 278(48): 48300 - 48312. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bastepe, Y. Gunes, B. Perez-Villamil, J. Hunzelman, L. S. Weinstein, and H. Juppner Receptor-Mediated Adenylyl Cyclase Activation Through XL{alpha}s, the Extra-Large Variant of the Stimulatory G Protein {alpha}-Subunit Mol. Endocrinol., August 1, 2002; 16(8): 1912 - 1919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Gensure, P. H. Carter, B. D. Petroni, H. Juppner, and T. J. Gardella Identification of Determinants of Inverse Agonism in a Constitutively Active Parathyroid Hormone/Parathyroid Hormone-related Peptide Receptor by Photoaffinity Cross-linking and Mutational Analysis J. Biol. Chem., November 9, 2001; 276(46): 42692 - 42699. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. P. Goold, T. B. Usdin, and S. R. J. Hoare Regions in Rat and Human Parathyroid Hormone (PTH) 2 Receptors Controlling Receptor Interaction with PTH and with Antagonist Ligands J. Pharmacol. Exp. Ther., November 1, 2001; 299(2): 678 - 690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shimizu, P. H. Carter, A. Khatri, J. T. Potts Jr., and T. J. Gardella Enhanced Activity in Parathyroid Hormone-(1-14) and -(1-11): Novel Peptides for Probing Ligand-Receptor Interactions Endocrinology, July 1, 2001; 142(7): 3068 - 3074. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. H. Carter, B. D. Petroni, R. C. Gensure, E. Schipani, J. T. Potts Jr., and T. J. Gardella Selective and Nonselective Inverse Agonists for Constitutively Active Type-1 Parathyroid Hormone Receptors: Evidence for Altered Receptor Conformations Endocrinology, April 1, 2001; 142(4): 1534 - 1545. [Abstract] [Full Text]
|
|
|
|
|
|
K. B. Jonsson, M. R. John, R. C. Gensure, T. J. Gardella, and H. Juppner Tuberoinfundibular Peptide 39 Binds to the Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor, but Functions as an Antagonist Endocrinology, February 1, 2001; 142(2): 704 - 709. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Gether Uncovering Molecular Mechanisms Involved in Activation of G Protein-Coupled Receptors Endocr. Rev., February 1, 2000; 21(1): 90 - 113. [Abstract] [Full Text]
|
|
|
|
|
|
P. H. Carter, M. Shimizu, M. D. Luck, and T. J. Gardella The Hydrophobic Residues Phenylalanine 184 and Leucine 187 in the Type-1 Parathyroid Hormone (PTH) Receptor Functionally Interact with the Amino-terminal Portion of PTH-(1-34) J. Biol. Chem., November 5, 1999; 274(45): 31955 - 31960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. H. Carter, H. Jüppner, and T. J. Gardella Studies of the N-Terminal Region of a Parathyroid Hormone-Related Peptide(1-36) Analog: Receptor Subtype-Selective Agonists, Antagonists, and Photochemical Cross-Linking Agents Endocrinology, November 1, 1999; 140(11): 4972 - 4981. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. Mannstadt, H. Juppner, and T. J. Gardella Receptors for PTH and PTHrP: their biological importance and functional properties Am J Physiol Renal Physiol, November 1, 1999; 277(5): F665 - F675. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Schipani, C. Langman, J. Hunzelman, M. Le Merrer, K. Y. Loke, M. J. Dillon, C. Silve, and H. Jüppner A Novel Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Mutation in Jansen's Metaphyseal Chondrodysplasia J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3052 - 3057. [Abstract] [Full Text]
|
|
|
|
|
|
V. Behar, A. Bisello, M. Rosenblatt, and M. Chorev Direct Identification of Two Contact Sites for Parathyroid Hormone (PTH) in the Novel PTH-2 Receptor using Photoaffinity Cross-Linking Endocrinology, September 1, 1999; 140(9): 4251 - 4261. [Abstract] [Full Text]
|
|
|
|
|
|
D. A. Rubin, P. Hellman, L. I. Zon, C. J. Lobb, C. Bergwitz, and H. Juppner A G Protein-coupled Receptor from Zebrafish Is Activated by Human Parathyroid Hormone and Not by Human or Teleost Parathyroid Hormone-related Peptide. IMPLICATIONS FOR THE EVOLUTIONARY CONSERVATION OF CALCIUM-REGULATING PEPTIDE HORMONES J. Biol. Chem., August 13, 1999; 274(33): 23035 - 23042. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Luck, P. H. Carter, and T. J. Gardella The (1-14) Fragment of Parathyroid Hormone (PTH) Activates Intact and Amino-Terminally Truncated PTH-1 Receptors Mol. Endocrinol., May 1, 1999; 13(5): 670 - 680. [Abstract] [Full Text]
|
|
|
|
|
|
T. H. Ji, M. Grossmann, and I. Ji G Protein-coupled Receptors. I. DIVERSITY OF RECEPTOR-LIGAND INTERACTIONS J. Biol. Chem., July 10, 1998; 273(28): 17299 - 17302. [Full Text] [PDF]
|
|
|
|
|
|
M. Mannstadt, M. D. Luck, T. J. Gardella, and H. Juppner Evidence for a Ligand Interaction Site at the Amino-Terminus of the Parathyroid Hormone (PTH)/PTH-related Protein Receptor from Cross-linking and Mutational Studies J. Biol. Chem., July 3, 1998; 273(27): 16890 - 16896. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. R. Turner, S. Mefford, T. Bambino, and R. A. Nissenson Transmembrane Residues Together with the Amino Terminus Limit the Response of the Parathyroid Hormone (PTH) 2 Receptor to PTH-related Peptide J. Biol. Chem., February 13, 1998; 273(7): 3830 - 3837. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Piserchio, T. Usdin, and D. F. Mierke Structure of Tuberoinfundibular Peptide of 39 Residues J. Biol. Chem., August 25, 2000; 275(35): 27284 - 27290. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. J. Hoare, J. A. Clark, and T. B. Usdin Molecular Determinants of Tuberoinfundibular Peptide of 39 Residues (TIP39) Selectivity for the Parathyroid Hormone-2 (PTH2) Receptor. N-TERMINAL TRUNCATION OF TIP39 REVERSES PTH2 RECEPTOR/PTH1 RECEPTOR BINDING SELECTIVITY J. Biol. Chem., August 25, 2000; 275(35): 27274 - 27283. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Gensure, T. J. Gardella, and H. Juppner Multiple Sites of Contact between the Carboxyl-terminal Binding Domain of PTHrP-(1-36) Analogs and the Amino-terminal Extracellular Domain of the PTH/PTHrP Receptor Identified by Photoaffinity Cross-linking J. Biol. Chem., July 27, 2001; 276(31): 28650 - 28658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Shimizu, J. Guo, and T. J. Gardella Parathyroid Hormone (PTH)-(1-14) and -(1-11) Analogs Conformationally Constrained by alpha -Aminoisobutyric Acid Mediate Full Agonist Responses via the Juxtamembrane Region of the PTH-1 Receptor J. Biol. Chem., December 21, 2001; 276(52): 49003 - 49012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Shimizu, J. T. Potts Jr., and T. J. Gardella Minimization of Parathyroid Hormone. NOVEL AMINO-TERMINAL PARATHYROID HORMONE FRAGMENTS WITH ENHANCED POTENCY IN ACTIVATING THE TYPE-1 PARATHYROID HORMONE RECEPTOR J. Biol. Chem., July 14, 2000; 275(29): 21836 - 21843. [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 |
