Salt as a catalyst in the mitochondria: returning cytochrome c to its native state after it misfolds on the surface of cardiolipin containing membranes

Pandiscia, Leah; Schweitzer‐Stenner, Reinhard

doi:10.1039/c3cc48709a

Cited by 22 publications

(31 citation statements)

References 23 publications

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“…89 At pH 7.4, 150 mM salt causes only partial dissociation of cytc from the CL ND. This behavior has previously been observed by other laboratories 43,87,88 and indicates that at pH 7.4 binding sites on cytc that have a significant hydrophobic component also contribute to binding.…”

Section: T H Isupporting

confidence: 92%

“…Many studies of binding of cyt c to CL-containing liposomes involve titration of cyt c , at concentrations that are near the K d , with increasing concentrations of CL typically in the form of liposomes. ,− Thus, accurate evaluation of K d requires correction for bound CL. Estimates of the number of CL molecules bound to each cyt c cover a large range. , Direct experimental determination of the CL:cyt c stoichiometry has shown that this stoichiometry depends on ionic strength and requires prior experimental determination of the effective charge on the protein, Z , and an intrinsic binding constant, K o , for the interaction from binding data as a function of salt concentration under low-binding conditions .…”

Section: Resultsmentioning

confidence: 99%

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The Human Cytochrome c Domain-Swapped Dimer Facilitates Tight Regulation of Intrinsic Apoptosis

et al. 2020

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Oxidation of cardiolipin (CL) by cytochrome c (cytc) has been proposed to initiate the intrinsic pathway of apoptosis. Domain-swapped dimer (DSD) conformations of cytc have been reported both by our laboratory and by others. The DSD is an alternate conformer of cytc that could oxygenate CL early in apoptosis. We demonstrate here that the cytc DSD has a set of properties that would provide tighter regulation of the intrinsic pathway. We show that the human DSD is kinetically more stable than horse and yeast DSDs. Circular dichroism data indicate that the DSD has a less asymmetric heme environment, similar to that seen when the monomeric protein binds to CL vesicles at high lipid:protein ratios. The dimer undergoes the alkaline conformational transition near pH 7.0, 2.5 pH units lower than that of the monomer. Data from fluorescence correlation spectroscopy and fluorescence anisotropy suggest that the alkaline transition of the DSD may act as a switch from a high affinity for CL nanodiscs at pH 7.4 to a much lower affinity at pH 8.0. Additionally, the peroxidase activity of the human DSD increases 7-fold compared to that of the monomer at pH 7 and 8, but by 14-fold at pH 6 when mixed Met80/H2O ligation replaces the lysine ligation of the alkaline state. We also present data that indicate that cytc binding shows a cooperative effect as the concentration of cytc is increased. The DSD appears to have evolved into a pH-inducible switch that provides a means to control activation of apoptosis near pH 7.0.

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Section: T H Isupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

The Human Cytochrome c Domain-Swapped Dimer Facilitates Tight Regulation of Intrinsic Apoptosis

et al. 2020

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“…Instead, the data seem to indicate that proteins undergo a transition from a non-native into a more native-like state. This picture did indeed emerge from the first analysis of Pandiscia and Schweitzer-Stenner (2014).…”

Section: Binding Studies With Varying Lipid Concentrationsmentioning

confidence: 80%

Relating the multi-functionality of cytochrome c to membrane binding and structural conversion

Schweitzer‐Stenner

2018

Biophys Rev

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Cytochrome c is known as an electron-carrying protein in the respiratory chain of mitochondria. Over the last 20 years, however, alternative functions of this very versatile protein have become the focus of research interests. Upon binding to anionic lipids such as cardiolipin, the protein acquires peroxidase activity. Multiple lines of evidence suggest that this requires a conformational change of the protein which involves partial unfolding of its tertiary structure. This review summarizes the current state of knowledge of how cytochrome c interacts with cardiolipin-containing surfaces and how this affects its structure and function. In this context, we delineate partially conflicting results regarding the affinity of cytochrome c binding to cardiolipin-containing liposomes of different size and its influence on the structure of the protein and the morphology of the membrane.

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“…First, none of the above studies probed the state of the unbound protein; hence it was not checked whether the conformational transition of the protein is really reversible. Very recently, Pandiscia and Schweitzer-Stenner found that this is not the case in the absence of salt [175]. Instead a major fraction of the protein stays in a semiunfolded state, exhibiting substantial tryptophan fluorescence.…”

Section: Unfolding Of Cytochrome C On Anionic Liposome Surfacesmentioning

confidence: 98%

Cytochrome c: A Multifunctional Protein Combining Conformational Rigidity with Flexibility

Schweitzer‐Stenner

2014

New Journal of Science

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Cytochrome has served as a model system for studying redox reactions, protein folding, and more recently peroxidase activity induced by partial unfolding on membranes. This review illuminates some important aspects of the research on this biomolecule. The first part summarizes the results of structural analyses of its active site. Owing to heme-protein interactions the heme group is subject to both in-plane and out-of-plane deformations. The unfolding of the protein as discussed in detail in the second part of this review can be induced by changes of pH and temperature and most prominently by the addition of denaturing agents. Both the kinetic and thermodynamic folding and unfolding involve intermediate states with regard to all unfolding conditions. If allowed to sit at alkaline pH (11.5) for a week, the protein does not return to its folding state when the solvent is switched back to neutral pH. It rather adopts a misfolded state that is prone to aggregation via domain swapping. On the surface of cardiolipin containing liposomes, the protein can adopt a variety of partially unfolded states. Apparently, ferricytochrome c can perform biological functions even if it is only partially folded.

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Salt as a catalyst in the mitochondria: returning cytochrome c to its native state after it misfolds on the surface of cardiolipin containing membranes

Abstract: Cytochrome c binding to cardiolipin receptors on the surface of TOCL/DOPC(20% : 80%) liposomes induces a conformational change, which is not reversible after the protein's dissociation at low ionic strength. Addition of 100 mM NaCl switches the protein back to its native state.

Cited by 22 publications

References 23 publications

The Human Cytochrome c Domain-Swapped Dimer Facilitates Tight Regulation of Intrinsic Apoptosis

The Human Cytochrome c Domain-Swapped Dimer Facilitates Tight Regulation of Intrinsic Apoptosis

Relating the multi-functionality of cytochrome c to membrane binding and structural conversion

Cytochrome c: A Multifunctional Protein Combining Conformational Rigidity with Flexibility

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