Nitric oxide and heat shock protein 90 activate soluble guanylate cyclase by driving rapid change in its subunit interactions and heme content

J Biol Chem. 2014 May 30;289(22):15259-71. doi: 10.1074/jbc.M114.559393. Epub 2014 Apr 14.


The chaperone heat shock protein 90 (hsp90) associates with signaling proteins in cells including soluble guanylate cyclase (sGC). hsp90 associates with the heme-free (apo) sGC-β1 subunit and helps to drive heme insertion during maturation of sGC to its NO-responsive active form. Here, we found that NO caused apo-sGC-β1 to rapidly and transiently dissociate from hsp90 and associate with sGC-α1 in cells. This NO response (i) required that hsp90 be active and that cellular heme be available and be capable of inserting into apo-sGC-β1; (ii) was associated with an increase in sGC-β1 heme content; (iii) could be mimicked by the heme-independent sGC activator BAY 60-2770; and (iv) was followed by desensitization of sGC toward NO, sGC-α1 disassociation, and reassociation with hsp90. Thus, NO promoted a rapid, transient, and hsp90-dependent heme insertion into the apo-sGC-β1 subpopulation in cells, which enabled it to combine with the sGC-α1 subunit to form the mature enzyme. The driving mechanism likely involves conformational changes near the heme site in sGC-β1 that can be mimicked by the pharmacologic sGC activator. Such dynamic interplay between hsp90, apo-sGC-β1, and sGC-α1 in response to NO is unprecedented and represent new steps by which cells can modulate the heme content and activity of sGC for signaling cascades.

Keywords: Guanylate Cyclase (Guanylyl Cyclase); Heme; Hsp90; Nitric Oxide; Nitrosative Stress; Signal Transduction.

Publication types

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

MeSH terms

  • Animals
  • Aorta / cytology
  • Benzoates / pharmacology
  • Biphenyl Compounds / pharmacology
  • COS Cells
  • Cattle
  • Chlorocebus aethiops
  • Dimerization
  • Endothelial Cells / cytology
  • Endothelial Cells / enzymology
  • Fibroblasts / cytology
  • Fibroblasts / enzymology
  • Guanylate Cyclase / chemistry
  • Guanylate Cyclase / genetics
  • Guanylate Cyclase / metabolism*
  • HSP90 Heat-Shock Proteins / agonists
  • HSP90 Heat-Shock Proteins / metabolism*
  • Heme / metabolism*
  • Humans
  • Hydrocarbons, Fluorinated / pharmacology
  • Lung / cytology
  • Nitric Oxide / metabolism*
  • Nitric Oxide Donors / pharmacology
  • Pyrazoles / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Soluble Guanylyl Cyclase


  • 3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
  • 4-(((4-carboxybutyl) (2- (5-fluoro-2-((4'-(trifluoromethyl) biphenyl-4-yl)methoxy)phenyl)ethyl) amino)methyl)benzoic acid
  • Benzoates
  • Biphenyl Compounds
  • HSP90 Heat-Shock Proteins
  • HSP90AA1 protein, human
  • Hydrocarbons, Fluorinated
  • Nitric Oxide Donors
  • Pyrazoles
  • Pyridines
  • Receptors, Cytoplasmic and Nuclear
  • Nitric Oxide
  • Heme
  • Guanylate Cyclase
  • Soluble Guanylyl Cyclase