A new paradigm for hormone recognition and allosteric receptor activation revealed from structural studies of NPR-C.
The natriuretic peptide system of hormones and receptors poses an abundance of interesting biophysical questions regarding receptor structure, hormone recognition, and receptor activation. Functional and biochemical data have implicated a series of conformational changes as the mechanism by which NP receptor activation is achieved. We have explored the structural basis of hormone recognition by the NP clearance receptor, termed NPR-C. While NPR-C does not contain the classical guanylyl-cyclase activity in its intracellular domains, its extracellular domain is highly similar to the GC-coupled members of this family. The 1:2 stoichiometry of hormone binding to NPR-C is also used by NPR-A and -B to bind hormones. The structure of NPR-C in both quiescent and hormone-bound forms reveals the hormone intercalates within the interface of a receptor dimer, inducing a large-scale conformational change in the membrane proximal regions. This mechanism of hormone recognition will be conserved across the entire NPR family. The allosteric response of the NPR-C ectodomain to ligand binding is likely a glimpse of the general activation signal of these receptors, despite their differing downstream signaling cascades. In this review, we discuss our results on NPR-C and their relevance to the NPR family as a whole, as well as its place as a basic new paradigm for receptor activation.
He
Xiao-Lin
XL
Department of Microbiology & Immunology, Stanford University School of Medicine, Fairchild D319, 299 Campus Drive, Stanford, CA 94305-5124, USA.
Dukkipati
Abhiram
A
Wang
Xinquan
X
Garcia
K Christopher
KC
D000495:Allosteric Site; D000818:Animals; D055592:Biophysical Phenomena; D001703:Biophysics; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017461:Receptors, Atrial Natriuretic Factor / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction
D008024:Ligands; D010455:Peptides; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C