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Nitric Oxide and Heat Shock Protein 90 Activate Soluble Guanylate Cyclase by Driving Rapid Change in Its Subunit Interactions and Heme Content
Authors:Arnab Ghosh  Johannes-Peter Stasch  Andreas Papapetropoulos  Dennis J Stuehr
Institution:From the Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio 44195.;§Bayer Pharma AG, Aprather Weg 18a, D-42096 Wuppertal, Germany, and ;the Department of Pharmacy, University of Patras, 26504 Patras, Greece
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
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