TAILIEUCHUNG - Báo cáo khoa học: In vivo degradation of nitric oxide synthase (NOS) and heat shock protein 90 (HSP90) by calpain is modulated by the formation of a NOS–HSP90 heterocomplex

We have shown previously that isolated heat shock protein 90 (HSP90) and nitric oxide synthase (NOS), once associated in a heterocomplex, become completely resistant to calpain digestion. In this study, it is shown that, in vivo, under conditions of calpain activation, the protection of NOS degradation occurs. | ỊFEBS Journal In vivo degradation of nitric oxide synthase NOS and heat shock protein 90 HSP90 by calpain is modulated by the formation of a NOS-HSP90 heterocomplex Monica Averna Roberto Stifanese Roberta De Tullio Franca Salamino Sandro Pontremoli and Edon Melloni Department of ExperimentalMedicine DIMES -Biochemistry Section and Centre of Excellence for BiomedicalResearch CEBR University of Genoa Italy Keywords Ca2 homeostasis calpain calpastatin heat shock protein 90 nitric oxide synthase Correspondence S. Pontremoli Department of Experimental Medicine DIMES -Biochemistry Section University of Genoa Viale Benedetto XV 1-16132 Genoa Italy Fax 39 010 518343 Tel 39 010 3538128 E-mail pontremoli@ Received 8 October 2007 revised 19 February 2008 accepted 11 March 2008 doi We have shown previously that isolated heat shock protein 90 HSP90 and nitric oxide synthase NOS once associated in a heterocomplex become completely resistant to calpain digestion. In this study it is shown that in vivo under conditions of calpain activation the protection of NOS degradation occurs. In addition the extent of NOS degradation is a function of the level of HSP90 expression. Thus in rat brain which contains a large excess of HSP90 almost all neuronal NOS is associated with the chaperone protein. In this condition neuronal NOS retains its full catalytic activity although limited proteolytic conversion to still active low-molecular-mass 130 kDa products takes place. In contrast in aorta which contains much smaller amounts of HSP90 endothelial NOS is not completely associated with the chaperone and undergoes extensive degradation with a loss of protein and catalytic activity. On the basis of these findings we propose a novel role of the HSP90-NOS heterocomplex in protecting in vivo NOS from proteolytic degradation by calpain. The efficiency of this effect is directly related to the level of intracellular HSP90 expression generating a high HSP90 to

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