Nitric oxide-induced conformational changes in soluble guanylate cyclase

Structure. 2014 Apr 8;22(4):602-11. doi: 10.1016/j.str.2014.01.008. Epub 2014 Feb 20.

Abstract

Soluble guanylate cyclase (sGC) is the primary mediator of nitric oxide (NO) signaling. NO binds the sGC heme cofactor stimulating synthesis of the second messenger cyclic-GMP (cGMP). As the central hub of NO/cGMP signaling pathways, sGC is important in diverse physiological processes such as vasodilation and neurotransmission. Nevertheless, the mechanisms underlying NO-induced cyclase activation in sGC remain unclear. Here, hydrogen/deuterium exchange mass spectrometry (HDX-MS) was employed to probe the NO-induced conformational changes of sGC. HDX-MS revealed NO-induced effects in several discrete regions. NO binding to the heme-NO/O2-binding (H-NOX) domain perturbs a signaling surface implicated in Per/Arnt/Sim (PAS) domain interactions. Furthermore, NO elicits striking conformational changes in the junction between the PAS and helical domains that propagate as perturbations throughout the adjoining helices. Ultimately, NO binding stimulates the catalytic domain by contracting the active site pocket. Together, these conformational changes delineate an allosteric pathway linking NO binding to activation of the catalytic domain.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Catalytic Domain
  • Cyclic GMP / chemistry*
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression
  • Guanylate Cyclase / chemistry*
  • Guanylate Cyclase / genetics
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Nitric Oxide / chemistry*
  • Protein Binding
  • Protein Folding
  • Protein Multimerization
  • Protein Structure, Secondary
  • Protein Subunits / chemistry*
  • Protein Subunits / genetics
  • Receptors, Cytoplasmic and Nuclear / chemistry*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Soluble Guanylyl Cyclase

Substances

  • Protein Subunits
  • Receptors, Cytoplasmic and Nuclear
  • Recombinant Proteins
  • Nitric Oxide
  • Guanylate Cyclase
  • Soluble Guanylyl Cyclase
  • Cyclic GMP