Allosteric activation of a spring-loaded natriuretic peptide receptor dimer by hormone.
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.
He Xl
Departments of Microbiology and Immunology and Structural Biology, Stanford University School of Medicine, Fairchild D319, 299 Campus Drive, Stanford, CA 93405-5124, USA.
Chow Dc
Martick
M M
MM
Garcia
K C
KC
D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D001665:Binding Sites; D002151:Calorimetry; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism; D003460:Crystallization; D018360:Crystallography, X-Ray; D019281:Dimerization; D004330:Drosophila; D006031:Glycosylation; D006162:Guanylate Cyclase / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D020098:Natriuretic Peptide, C-Type / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017461:Receptors, Atrial Natriuretic Factor / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics
D002712:Chlorides; D008024:Ligands; D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type; D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C