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Received for publication March 9, 2005.
Revised July 8, 2005.
Accepted for publication July 8, 2005.
Heat shock protein 90 (hsp90) regulates stability and function of many client proteins including members of the NO-cGMP signaling pathway. Soluble guanylyl cyclase (sGC), a nitric oxide (NO) receptor, was recently reported to be an hsp90 interacting partner. In the present study, we show that hsp90 binds to both subunits of the most common sGC form (
1
1) when these are expressed individually, but only interacts with 1 in the heterodimeric form of the enzyme. Characterization of the region of hsp90 required to bind each subunit in immunoprecipitation experiments, revealed that residues 310-456 of hsp90 interact with the sGC subunits. The region of 1 responsible for binding to hsp90 was mapped using in vitro binding assays and immunoprecipitation experiments and found to lie in the regulatory domain. The physiological importance of the hsp90/sGC interaction was investigated by treating rat smooth muscle cells (RASMC) with the hsp90 inhibitors radicicol (RAD) and geldanamycin (GA) and determining both sGC activity and protein levels. Long-term (24 or 48hr) inhibition of hsp90 resulted in a strong decrease of both 1 and 1 protein levels, as well as sGC activity. Moreover, incubation of smooth muscle cells with the proteasome inhibitor MG132 blocked the GA-induced downregulation of sGC. We conclude that the N-terminal region of the 1 subunit mediates binding of the heterodimeric form of sGC to hsp90 and that this interaction involves the M domain of hsp90. Hsp90 binding to sGC regulates the pool of active enzyme by affecting the protein levels of the two subunits.
Key words:
Guanylyl cyclase, Nitric oxide
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