Soluble guanylyl cyclase requires heat shock protein 90 for heme insertion during maturation of the NO-active enzyme
- 25 July 2012
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (32), 12998-13003
- https://doi.org/10.1073/pnas.1205854109
Abstract
Heme insertion is key during maturation of soluble guanylyl cyclase (sGC) because it enables sGC to recognize NO and transduce its multiple biological effects. Although sGC is often associated with the 90-kDa heat shock protein (hsp90) in cells, the implications are unclear. The present study reveals that hsp90 is required to drive heme insertion into sGC and complete its maturation. We used a mammalian cell culture approach and followed heme insertion into transiently and endogenously expressed heme-free sGC. We used pharmacological hsp90 inhibitors, an ATP-ase inactive hsp90 mutant, and heme-dependent or heme-independent sGC activators as tools to decipher the role of hsp90. Our findings suggest that hsp90 complexes with apo-sGC, drives heme insertion through its inherent ATPase activity, and then dissociates from the mature, heme-replete sGC. Together, this improves our understanding of sGC maturation and reveals a unique means to control sGC activity in cells, and it has important implications for hsp90 inhibitor-based cancer therapy.Keywords
This publication has 42 references indexed in Scilit:
- Diverse Cellular Functions of the Hsp90 Molecular Chaperone Uncovered Using Systems ApproachesCell, 2007
- NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potentialNature Reviews Drug Discovery, 2006
- Structure and Mechanism of the Hsp90 Molecular Chaperone MachineryAnnual Review of Biochemistry, 2006
- The Role of hsp90 in Heme-dependent Activation of Apo-neuronal Nitric-oxide SynthasePublished by Elsevier BV ,2004
- Hsp90 isoforms: functions, expression and clinical importanceFEBS Letters, 2004
- Heat Shock Protein 90 as an Endogenous Protein Enhancer of Inducible Nitric-oxide SynthasePublished by Elsevier BV ,2003
- Domain Mapping Studies Reveal That the M Domain of hsp90 Serves as a Molecular Scaffold to Regulate Akt-Dependent Phosphorylation of Endothelial Nitric Oxide Synthase and NO ReleaseCirculation Research, 2002
- Structure of Nitric Oxide Synthase Oxygenase Dimer with Pterin and SubstrateScience, 1998
- cAMP regulates soluble guanylate cyclase beta 1-subunit gene expression in RFL-6 rat fetal lung fibroblastsAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 1993
- Activation of purified guanylate cyclase by nitric oxide requires heme comparison of heme-deficient, heme-reconstituted and heme-containing forms of soluble enzyme from bovine lungBiochimica et Biophysica Acta (BBA) - General Subjects, 1982