Impact of Actin Glutathionylation on the Actomyosin-S1 ATPase

Pizarro, Gresin O.; Ogut, Ozgur

doi:10.1021/bi900669m

Cited by 21 publications

(14 citation statements)

References 35 publications

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“…A cuvette containing 0.5 μM RIα with 2 nM 8-fluo-cAMP in 150 mM KCl, 20 mM PIPES, pH 7 was serially diluted with 2 nM 8-fluo-cAMP in 150 mM KCl, 20 mM PIPES, pH 7 to measure the anisotropy vs. RIα concentration. Binding curves were fit individually to determine the Kd for each titration, as previously described [28,33]. …”

Section: Methodsmentioning

confidence: 99%

Human heart failure is accompanied by altered protein kinase A subunit expression and post-translational state

Han

Arroyo

Ogut

2013

Archives of Biochemistry and Biophysics

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β-Adrenergic receptor blockade reduces total mortality and all-cause hospitalizations in patients with heart failure (HF). Nonetheless, β-blockade does not halt disease progression, suggesting that cAMP-dependent protein kinase (PKA) signaling downstream of β-adrenergic receptor activation may persist through unique post-translational states. In this study, human myocardial tissue was used to examine the state of PKA subunits. As expected, total myosin binding protein-C phosphorylation and Ser23/24 troponin I phosphorylation significantly decreased in HF. Examination of PKA subunits demonstrated no change in type II regulatory (RIIα) or catalytic (Cα) subunit expression, although site specific RIIα (Ser96) and Cα (Thr197) phosphorylation were increased in HF. Further, the expression of type I regulatory subunit (RI) was increased in HF. Isoelectric focusing of RIα demonstrated up to three variants, consistent with reports that Ser77 and Ser83 are in vivo phosphorylation sites. Western blots with site-specific monoclonal antibodies showed increased Ser83 phosphorylation in HF. 8-fluo-cAMP binding by wild type and phosphomimic Ser77 and Ser83 mutant RIα proteins demonstrated reduced Kd for the double mutant as compared to WT RIα. Therefore, failing myocardium displays altered expression and post-translational modification of PKA subunits that may impact downstream signaling.

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Section: Methodsmentioning

confidence: 99%

Human heart failure is accompanied by altered protein kinase A subunit expression and post-translational state

Han

Arroyo

Ogut

2013

Archives of Biochemistry and Biophysics

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“…The low sensitivity of this antibody imparts a limited detection potential, and many of the proteins identified are abundant, e.g. actin (95), tubulin (96), and HSP70 (93). Immunoprecipitation followed by immunoblotting with the anti-GSH antibodies can enhance detection (89).…”

Section: Techniques For Measuring S-glutathionylationmentioning

confidence: 99%

Causes and Consequences of Cysteine S-Glutathionylation

Grek¹,

Zhang²,

Manevich³

et al. 2013

Journal of Biological Chemistry

278

275

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Post-translational S-glutathionylation occurs through the reversible addition of a proximal donor of glutathione to thiolate anions of cysteines in target proteins, where the modification alters molecular mass, charge, and structure/function and/or prevents degradation from sulfhydryl overoxidation or proteolysis. Catalysis of both the forward (glutathione S-transferase P) and reverse (glutaredoxin) reactions creates a functional cycle that can also regulate certain protein functional clusters, including those involved in redox-dependent cell signaling events. For translational application, S-glutathionylated serum proteins may be useful as biomarkers in individuals (who may also have polymorphic expression of glutathione S-transferase P) exposed to agents that cause oxidative or nitrosative stress.S-Glutathionylation targets cysteines in a basic environment (low pK a ) perhaps in close three-dimensional proximity to Arg, His, or Lys residues. Reports of reversible S-glutathionylation emerged as early as 1985 (1), but in concert with understanding the importance of reactive oxygen/nitrogen species (ROS/ RNS) 2 as second messengers, publications have increased substantially over the past 10 years. ROS/RNS signaling operates through a set of post-translational protein modifications that are discrete, site-specific, and reversible. Certain proteins undergo reversible chemical changes in response to altered localized redox potential. Among the most susceptible redoxsensitive targets are thiol (-SH) groups on cysteines. Signaling events are facilitated through redox-active proteins when one or more cysteines can exist as reactive thiolate anions. These cysteines are more nucleophilic and become susceptible to attack by GSH.Oxygen-based metabolism is arguably the most efficient and evolved method for producing energy from nutrients, but ROS

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“…Noteworthy, the deglutathionylation of G-actin leads to a six-fold increase in the rate of polymerization (Wang et al 2001), indicating the importance of reversible glutathionylation for sarcomere assembly. Additionally, actin glutathionylation was demonstrated to reduce actomyosin ATPase activity via the substitution of glutathionylated F-actin for unmodified F-actin (Pizarro and Ogut 2009).…”

Section: Impact Of Oxidative Stress On Cardiomyocyte Stiffness Sarcommentioning

confidence: 99%

A change of heart: oxidative stress in governing muscle function?

Breitkreuz

Hamdani

2015

Biophys Rev

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Redox/cysteine modification of proteins that regulate calcium cycling can affect contraction in striated muscles. Understanding the nature of these modifications would present the possibility of enhancing cardiac function through reversible cysteine modification of proteins, with potential therapeutic value in heart failure with diastolic dysfunction. Both heart failure and muscular dystrophy are characterized by abnormal redox balance and nitrosative stress. Recent evidence supports the synergistic role of oxidative stress and inflammation in the progression of heart failure with preserved ejection fraction, in concert with endothelial dysfunction and impaired nitric oxide-cyclic guanosine monophosphate-protein kinase G signalling via modification of the giant protein titin. Although antioxidant therapeutics in heart failure with diastolic dysfunction have no marked beneficial effects on the outcome of patients, it, however, remains critical to the understanding of the complex interactions of oxidative/nitrosative stress with pro-inflammatory mechanisms, metabolic dysfunction, and the redox modification of proteins characteristic of heart failure. These may highlight novel approaches to therapeutic strategies for heart failure with diastolic dysfunction. In this review, we provide an overview of oxidative stress and its effects on pathophysiological pathways. We describe the molecular mechanisms driving oxidative modification of proteins and subsequent effects on contractile function, and, finally, we discuss potential therapeutic opportunities for heart failure with diastolic dysfunction.

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Impact of Actin Glutathionylation on the Actomyosin-S1 ATPase

Cited by 21 publications

References 35 publications

Human heart failure is accompanied by altered protein kinase A subunit expression and post-translational state

Human heart failure is accompanied by altered protein kinase A subunit expression and post-translational state

Causes and Consequences of Cysteine S-Glutathionylation

A change of heart: oxidative stress in governing muscle function?

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