S-nitrosylation affects TRAP1 structure and ATPase activity and modulates cell response to apoptotic stimuli

Abstract

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TRAP1: A Metabolic Hub Linking Aging Pathophysiology to Mitochondrial S-Nitrosylation

“…Besides this regulation, it has also been very recently reported that S-nitrosylation of Cys501 produces a decrease of TRAP1 ATPase activity likely through an allosteric mechanism (Faienza et al, 2020). ATPase assays, together with molecular dynamics simulations, indicate that S-nitrosylation negatively impacts TRAP1 activity i) directly, through intra-and interprotomer long-range communication events that exert distal effects on the active site, and ii) indirectly, through the regulation of open-to-close state transition, which is crucial for this class of chaperones to complete the ATPase cycle (Faienza et al, 2020). Cells expressing a mutant form of TRAP1, in which Cys501 is substituted by a serine (C501S), are more resistant to mitochondrial toxins and to staurosporine-induced apoptosis (Faienza et al, 2020), suggesting that S-nitrosylation of Cys501 impacts TRAP1 biology.…”

“…ATPase assays, together with molecular dynamics simulations, indicate that S-nitrosylation negatively impacts TRAP1 activity i) directly, through intra-and interprotomer long-range communication events that exert distal effects on the active site, and ii) indirectly, through the regulation of open-to-close state transition, which is crucial for this class of chaperones to complete the ATPase cycle (Faienza et al, 2020). Cells expressing a mutant form of TRAP1, in which Cys501 is substituted by a serine (C501S), are more resistant to mitochondrial toxins and to staurosporine-induced apoptosis (Faienza et al, 2020), suggesting that S-nitrosylation of Cys501 impacts TRAP1 biology. Integrating these pieces of evidence, it is reasonable to propose that S-nitrosylation-induced degradation of TRAP1 is a direct consequence of its loss of activity.…”

The Mitochondrial Hsp90 TRAP1 and Alzheimer’s Disease

“…The cysteine can change the conformation of TRAP1 during its catalytic cycle, as determined by molecular dynamics simulations (Faienza et al, 2020). It also enables the interaction with client proteins (Faienza et al, 2020). This PTM has an inhibitory effect on the ATPase activity, which is in line with the protective role of TRAP1 in apoptosis (Faienza et al, 2020).…”

“…PTMs play an important role in the regulation of TRAP1, including (de)acetylation, (de)phosphorylation, S-nitrosylation and ubiquitination (Table 1) (Anckar and Sistonen, 2011;Matassa et al, 2012;Faienza et al, 2020). Similar to HSP90, phosphorylation contributes to activation of TRAP1 (Trepel et al, 2010;Anckar and Sistonen, 2011).…”

“…S-nitrosylation of Cys501 by S-nitrosylase complexes is associated with proteasomal degradation (Rizza et al, 2016). The cysteine can change the conformation of TRAP1 during its catalytic cycle, as determined by molecular dynamics simulations (Faienza et al, 2020). It also enables the interaction with client proteins (Faienza et al, 2020).…”