Investigation of structural dynamics of Thrombocytopenia Cargeeg mutants of human apoptotic cytochrome c : A molecular dynamics simulation approach

Muneeswaran, Gurusamy; Kartheeswaran, Subramanian; Manickam, Pandiaraj; Muthukumar, Kaliappan; Sankaralingam, Muniyandi; Arunachalam, S.

doi:10.1016/j.bpc.2017.09.004

Cited by 14 publications

(17 citation statements)

References 37 publications

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“…A recent study on the Tyr48His variant showed that the pentacoordinated form of Cytc, which promotes cardiolipin peroxidase activity, is more prevalent in the mutant, further supporting the increased apoptotic activity (71). Molecular dynamics simulations concluded that both Gly41Ser and Tyr48His mutations result in a less stable and more open protein structure, which would promote cardiolipin peroxidase activity (72). At this point, it is unclear why these mutations cause such a cell-type-specific phenotype.…”

Section: Tyr48 Phosphorylationmentioning

confidence: 97%

Tissue‐specific regulation of cytochrome c by post‐translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis

et al. 2018

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Cytochrome c (Cytc) plays a vital role in the mitochondrial electron transport chain (ETC). In addition, it is a key regulator of apoptosis. Cytc has multiple other functions including ROS production and scavenging, cardiolipin peroxidation, and mitochondrial protein import. Cytc is tightly regulated by allosteric mechanisms, tissue‐specific isoforms, and post‐translational modifications (PTMs). Distinct residues of Cytc are modified by PTMs, primarily phosphorylations, in a highly tissue‐specific manner. These modifications downregulate mitochondrial ETC flux and adjust the mitochondrial membrane potential (ΔΨm), to minimize reactive oxygen species (ROS) production under normal conditions. In pathologic and acute stress conditions, such as ischemia–reperfusion, phosphorylations are lost, leading to maximum ETC flux, ΔΨm hyperpolarization, excessive ROS generation, and the release of Cytc. It is also the dephosphorylated form of the protein that leads to maximum caspase activation. We discuss the complex regulation of Cytc and propose that it is a central regulatory step of the mammalian ETC that can be rate limiting in normal conditions. This regulation is important because it maintains optimal intermediate ΔΨm, limiting ROS generation. We examine the role of Cytc PTMs, including phosphorylation, acetylation, methylation, nitration, nitrosylation, and sulfoxidation and consider their potential biological significance by evaluating their stoichiometry.—Kalpage, H. A., Bazylianska, V., Recanati, M. A., Fite, A., Liu, J., Wan, J., Mantena, N., Malek, M. H., Podgorski, I., Heath, E. I., Vaishnav, A., Edwards, B. F., Grossman, L. I., Sanderson, T. H., Lee, I., Hüttemann, M. Tissue‐specific regulation of cytochrome c by post‐translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis. FASEB J. 33, 1540–1553 (2019). http://www.fasebj.org

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Section: Tyr48 Phosphorylationmentioning

confidence: 97%

Tissue‐specific regulation of cytochrome c by post‐translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis

et al. 2018

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“…Previous structural analyses showed that two mutations in the Ω‐loop (p.Gly42Ser and p.Tyr49His) of CYCS disrupted hydrogen bonds . As such, p.Lys101del may also disrupt the structural integrity of the protein by inserting the hydrophilic Thr103 residue into the position usually occupied by the hydrophobic Ala102 residue, which in turn would result in a deleterious effect on protein function and cellular phenotype . Importantly, the corresponding p.Lys105del had a similar effect to the deletion strain ( cyc1 Δ) in a yeast model, suggesting the loss‐of‐function (or null) nature of this variant with respect to energy metabolism.…”

Section: Discussionmentioning

confidence: 93%

“…All three reported missense mutations are clustered within the highly conserved Ω‐loop (Figure D) . Although in silico analysis suggested the significant structural impact of p.Lys101del, it is arguable that one amino acid in‐frame deletion outside the Ω‐loop would have a mild or neutral effect.…”

Section: Resultsmentioning

confidence: 99%

“…Both the hydrogen bond network and hydrophobic core are crucial elements of this protein's structure, function, and stability. Previous structural analyses showed that two mutations in the Ω‐loop (p.Gly42Ser and p.Tyr49His) of CYCS disrupted hydrogen bonds . As such, p.Lys101del may also disrupt the structural integrity of the protein by inserting the hydrophilic Thr103 residue into the position usually occupied by the hydrophobic Ala102 residue, which in turn would result in a deleterious effect on protein function and cellular phenotype .…”

Section: Discussionmentioning

confidence: 99%

“…10 All three reported missense mutations are clustered within the highly conserved Ω-loop ( Figure 1D). 3,11,12 Although in silico analysis suggested the significant structural impact of p.Lys101del, it is arguable that one amino acid in-frame deletion outside the Ω-loop would have a mild or neutral effect. To verify the pathogenicity of this variant in the less characterized C-terminal region, we used the fission yeast Schizosaccharomyces pombe as a model system.…”

Section: Wes Of Ii-4 Identified a Novel Heterozygous Variant In Cycsmentioning

confidence: 99%

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A novel CYCS mutation in the α‐helix of the CYCS C‐terminal domain causes non‐syndromic thrombocytopenia

et al. 2018

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We report a patient with thrombocytopenia from a Japanese family with hemophilia A spanning four generations. Various etiologies of thrombocytopenia, including genetic, immunological, and hematopoietic abnormalities, determine the prognosis for this disease. In this study, we identified a novel heterozygous mutation in a gene encoding cytochrome c, somatic (CYCS, MIM123970) using whole exome sequencing. This variant (c.301_303del:p.Lys101del) is located in the α-helix of the cytochrome c (CYCS) C-terminal domain. In silico structural analysis suggested that this mutation results in protein folding instability. CYCS is one of the key factors regulating the intrinsic apoptotic pathway and the mitochondrial respiratory chain. Using the yeast model system, we clearly demonstrated that this one amino acid deletion (in-frame) resulted in significantly reduced cytochrome c protein expression and functional defects in the mitochondrial respiratory chain, indicating that the loss of function of cytochrome c underlies thrombocytopenia. The clinical features of known CYCS variants have been reported to be confined to mild or asymptomatic thrombocytopenia, as was observed for the patient in our study. This study clearly demonstrates that thrombocytopenia can result from CYCS loss-of-function variants.

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Molecular insights on the conformational dynamics of a P76C mutant of human cytochrome c and the enhancement on its peroxidase activity

Samsri

Prasertsuk

Nutho

et al. 2022

Archives of Biochemistry and Biophysics

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Investigation of structural dynamics of Thrombocytopenia Cargeeg mutants of human apoptotic cytochrome c : A molecular dynamics simulation approach

Cited by 14 publications

References 37 publications

Tissue‐specific regulation of cytochrome c by post‐translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis

Tissue‐specific regulation of cytochrome c by post‐translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis

A novel CYCS mutation in the α‐helix of the CYCS C‐terminal domain causes non‐syndromic thrombocytopenia

Molecular insights on the conformational dynamics of a P76C mutant of human cytochrome c and the enhancement on its peroxidase activity

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