Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 293 (5535): 1657-1662

Copyright © 2001 by the American Association for the Advancement of Science

Allosteric Activation of a Spring-Loaded Natriuretic Peptide Receptor Dimer by Hormone

Xiao-lin He, Dar-chone Chow, Monika M. Martick, K. Christopher Garcia*

Natriuretic peptides (NPs) are vasoactive cyclic-peptide hormones important in blood pressure regulation through interaction with natriuretic cell-surface receptors. We report the hormone-binding thermodynamics and crystal structures at 2.9 and 2.0 angstroms, respectively, of the extracellular domain of the unliganded human NP receptor (NPR-C) and its complex with CNP, a 22-amino acid NP. A single CNP molecule is bound in the interface of an NPR-C dimer, resulting in asymmetric interactions between the hormone and the symmetrically related receptors. Hormone binding induces a 20 angstrom closure between the membrane-proximal domains of the dimer. In each monomer, the opening of an interdomain cleft, which is tethered together by a linker peptide acting as a molecular spring, is likely a conserved allosteric trigger for intracellular signaling by the natriuretic receptor family.

Departments of Microbiology and Immunology and Structural Biology, Stanford University School of Medicine, Fairchild D319, 299 Campus Drive, Stanford, CA 93405-5124, USA.
*   To whom correspondence should be addressed. E-mail: kcgarcia{at}

Natriuretic Peptide Receptor-3 Gene (NPR3): Nonsynonymous Polymorphism Results in Significant Reduction in Protein Expression Because of Accelerated Degradation.
N. L. Pereira, D. Lin, L. Pelleymounter, I. Moon, G. Stilling, B. W. Eckloff, E. D. Wieben, M. M. Redfield, J. C. Burnett Jr, V. C. Yee, et al. (2013)
Circ Cardiovasc Genet 6, 201-210
   Abstract »    Full Text »    PDF »
Site-specific N-Linked Glycosylation of Receptor Guanylyl Cyclase C Regulates Ligand Binding, Ligand-mediated Activation and Interaction with Vesicular Integral Membrane Protein 36, VIP36.
N. Arshad, S. Ballal, and S. S. Visweswariah (2013)
J. Biol. Chem. 288, 3907-3917
   Abstract »    Full Text »    PDF »
The C-Type Natriuretic Peptide Induces Thermal Hyperalgesia through a Noncanonical G{beta}{gamma}-dependent Modulation of TRPV1 Channel.
L. Loo, A. J. Shepherd, A. D. Mickle, R. A. Lorca, L. P. Shutov, Y. M. Usachev, and D. P. Mohapatra (2012)
J. Neurosci. 32, 11942-11955
   Abstract »    Full Text »    PDF »
Molecular basis of positive allosteric modulation of GluN2B NMDA receptors by polyamines.
L. Mony, S. Zhu, S. Carvalho, and P. Paoletti (2011)
EMBO J. 30, 3134-3146
   Abstract »    Full Text »    PDF »
Dynamics and allosteric potential of the AMPA receptor N-terminal domain.
M. Sukumaran, M. Rossmann, I. Shrivastava, A. Dutta, I. Bahar, and I. H. Greger (2011)
EMBO J. 30, 972-982
   Abstract »    Full Text »    PDF »
Crystal structure and association behaviour of the GluR2 amino-terminal domain.
R. Jin, S. K. Singh, S. Gu, H. Furukawa, A. I. Sobolevsky, J. Zhou, Y. Jin, and E. Gouaux (2009)
EMBO J. 28, 1812-1823
   Abstract »    Full Text »    PDF »
Design and characterization of a soluble fragment of the extracellular ligand-binding domain of the peptide hormone receptor guanylyl cyclase-C.
T. Lauber, N. Tidten, I. Matecko, M. Zeeb, P. Rosch, and U.C. Marx (2009)
Protein Eng. Des. Sel. 22, 1-7
   Abstract »    Full Text »    PDF »
Functioning of the dimeric GABAB receptor extracellular domain revealed by glycan wedge scanning.
P. Rondard, S. Huang, C. Monnier, H. Tu, B. Blanchard, N. Oueslati, F. Malhaire, Y. Li, E. Trinquet, G. Labesse, et al. (2008)
EMBO J. 27, 1321-1332
   Abstract »    Full Text »    PDF »
Role of Extracellular Domain Dimerization in Agonist-Induced Activation of Natriuretic Peptide Receptor A.
M. Parat, N. McNicoll, B. Wilkes, A. Fournier, and A. De Lean (2008)
Mol. Pharmacol. 73, 431-440
   Abstract »    Full Text »    PDF »
Natriuretic peptide C receptor signalling in the heart and vasculature.
R. A. Rose and W. R. Giles (2008)
J. Physiol. 586, 353-366
   Abstract »    Full Text »    PDF »
Osteocrin Is a Specific Ligand of the Natriuretic Peptide Clearance Receptor That Modulates Bone Growth.
P. Moffatt, G. Thomas, K. Sellin, M.-C. Bessette, F. Lafreniere, O. Akhouayri, R. St-Arnaud, and C. Lanctot (2007)
J. Biol. Chem. 282, 36454-36462
   Abstract »    Full Text »    PDF »
Conformational and thermodynamic changes of the repressor/DNA operator complex upon monomerization shed new light on regulation mechanisms of bacterial resistance against {beta}-lactam antibiotics.
J. Boudet, V. Duval, H. Van Melckebeke, M. Blackledge, A. Amoroso, B. Joris, and J.-P. Simorre (2007)
Nucleic Acids Res. 35, 4384-4395
   Abstract »    Full Text »    PDF »
International Union of Basic and Clinical Pharmacology. LXVII. Recommendations for the Recognition and Nomenclature of G Protein-Coupled Receptor Heteromultimers.
J.-P. Pin, R. Neubig, M. Bouvier, L. Devi, M. Filizola, J. A. Javitch, M. J. Lohse, G. Milligan, K. Palczewski, M. Parmentier, et al. (2007)
Pharmacol. Rev. 59, 5-13
   Abstract »    Full Text »    PDF »
Dual signaling is differentially activated by different active states of the metabotropic glutamate receptor 1{alpha}.
M. Tateyama and Y. Kubo (2006)
PNAS 103, 1124-1128
   Abstract »    Full Text »    PDF »
Crystal Structure of Hormone-bound Atrial Natriuretic Peptide Receptor Extracellular Domain: ROTATION MECHANISM FOR TRANSMEMBRANE SIGNAL TRANSDUCTION.
H. Ogawa, Y. Qiu, C. M. Ogata, and K. S. Misono (2004)
J. Biol. Chem. 279, 28625-28631
   Abstract »    Full Text »    PDF »
Stoichiometry of the T-cell receptor-CD3 complex and key intermediates assembled in the endoplasmic reticulum.
M. E. Call, J. Pyrdol, and K. W. Wucherpfennig (2004)
EMBO J. 23, 2348-2357
   Abstract »    Full Text »    PDF »
Structure of Nerve Growth Factor Complexed with the Shared Neurotrophin Receptor p75.
X.-l. He and K. C. Garcia (2004)
Science 304, 870-875
   Abstract »    Full Text »    PDF »
Adenylyl Cyclase G Is Activated by an Intramolecular Osmosensor.
S. Saran and P. Schaap (2004)
Mol. Biol. Cell 15, 1479-1486
   Abstract »    Full Text »    PDF »
Constitutive Activation and Uncoupling of the Atrial Natriuretic Peptide Receptor by Mutations at the Dimer Interface: ROLE OF THE DIMER STRUCTURE IN SIGNALING.
Y. Qiu, H. Ogawa, M. Miyagi, and K. S. Misono (2004)
J. Biol. Chem. 279, 6115-6123
   Abstract »    Full Text »    PDF »
Locking the Dimeric GABAB G-Protein-Coupled Receptor in Its Active State.
J. Kniazeff, P.-P. Saintot, C. Goudet, J. Liu, A. Charnet, G. Guillon, and J.-P. Pin (2004)
J. Neurosci. 24, 370-377
   Abstract »    Full Text »    PDF »
Inhibition of L-type Ca2+ current by C-type natriuretic peptide in bullfrog atrial myocytes: an NPR-C-mediated effect.
R. A. Rose, A. E. Lomax, and W. R. Giles (2003)
Am J Physiol Heart Circ Physiol 285, H2454-H2462
   Abstract »    Full Text »    PDF »
Four functionally distinct C-type natriuretic peptides found in fish reveal evolutionary history of the natriuretic peptide system.
K. Inoue, K. Naruse, S. Yamagami, H. Mitani, N. Suzuki, and Y. Takei (2003)
PNAS 100, 10079-10084
   Abstract »    Full Text »    PDF »
Solution Structure of Human Proguanylin: THE ROLE OF A HORMONE PROSEQUENCE.
T. Lauber, P. Neudecker, P. Rosch, and U. C. Marx (2003)
J. Biol. Chem. 278, 24118-24124
   Abstract »    Full Text »    PDF »
Signaling Receptome: A Genomic and Evolutionary Perspective of Plasma Membrane Receptors Involved in Signal Transduction.
I. Ben-Shlomo, S. Yu Hsu, R. Rauch, H. W. Kowalski, and A. J. W. Hsueh (2003)
Sci. STKE 2003, re9
   Abstract »    Full Text »    PDF »
Natriuretic Peptide Receptor A Activation Stabilizes a Membrane-distal Dimer Interface.
A. De Lean, N. McNicoll, and J. Labrecque (2003)
J. Biol. Chem. 278, 11159-11166
   Abstract »    Full Text »    PDF »
Stabilizing the open conformation of the integrin headpiece with a glycan wedge increases affinity for ligand.
B.-H. Luo, T. A. Springer, and J. Takagi (2003)
PNAS 100, 2403-2408
   Abstract »    Full Text »    PDF »
Release of C-type natriuretic peptide accounts for the biological activity of endothelium-derived hyperpolarizing factor.
S. D. Chauhan, H. Nilsson, A. Ahluwalia, and A. J. Hobbs (2003)
PNAS 100, 1426-1431
   Abstract »    Full Text »    PDF »
No Ligand Binding in the GB2 Subunit of the GABAB Receptor Is Required for Activation and Allosteric Interaction between the Subunits.
J. Kniazeff, T. Galvez, G. Labesse, and J.-P. Pin (2002)
J. Neurosci. 22, 7352-7361
   Abstract »    Full Text »    PDF »
Closure of the Venus flytrap module of mGlu8 receptor and the activation process: Insights from mutations converting antagonists into agonists.
A.-S. Bessis, P. Rondard, F. Gaven, I. Brabet, N. Triballeau, L. Prezeau, F. Acher, and J.-P. Pin (2002)
PNAS 99, 11097-11102
   Abstract »    Full Text »    PDF »
Mapping the Binding Site of the Neuroprotectant Ifenprodil on NMDA Receptors.
F. Perin-Dureau, J. Rachline, J. Neyton, and P. Paoletti (2002)
J. Neurosci. 22, 5955-5965
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882