A new paradigm for hormone recognition and allosteric receptor activation revealed from structural studies of NPR-C

Xiao Lin He, Abhiram Dukkipati, Xinquan Wang, K. Christopher Garcia*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1035-1043
Number of pages9
JournalPeptides
Volume26
Issue number6 SPEC. ISS.
DOIs
StatePublished - Jun 2005

Keywords

  • Crystallography
  • Protein-protein interaction
  • Receptor
  • Signaling
  • Structure

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Endocrinology
  • Cellular and Molecular Neuroscience

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