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

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

Author information

1
From the Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio 44195.
2
Bayer Pharma AG, Aprather Weg 18a, D-42096 Wuppertal, Germany, and.
3
the Department of Pharmacy, University of Patras, 26504 Patras, Greece.
4
From the Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio 44195, stuehrd@ccf.org.

Abstract

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

PMID:
24733395
PMCID:
PMC4140884
DOI:
10.1074/jbc.M114.559393
[Indexed for MEDLINE]
Free PMC Article

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