Multifaceted Effects of ATP on Cardiolipin-Bound Cytochrome <i>c</i>

Snider, Erik J.; Muenzner, Julia; Toffey, Jason R.; Hong, Yuning; Pletneva, Ekaterina V.

doi:10.1021/bi301682c

Cited by 25 publications

(40 citation statements)

References 27 publications

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“…25,90–92 Mutations at residue 67 increase peroxidase activity of cyt c . 93 Previous work has suggested that Asn52 is close to one of the CL-binding sites in the protein (Figure 9b), 94,95 specifically to the location where CL acyl chains could possibly insert into the cyt c interior. 96 Consistent with this residue being a gate to the protein interior, replacement of Asn52 with a more hydrophobic and bulky Ile removes the internal water molecule from the hydrogen-bonding network, rigidifies the protein structure, increases the protein stability, and shifts the alkaline transition to higher pH.…”

Section: Discussionmentioning

confidence: 96%

A Compact Structure of Cytochrome c Trapped in a Lysine-Ligated State: Loop Refolding and Functional Implications of a Conformational Switch

et al. 2015

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It has been suggested that the alkaline form of cytochrome c (cyt c) regulates function of this protein as an electron carrier in oxidative phosphorylation and as a peroxidase that reacts with cardiolipin (CL) during apoptosis. In this form, Met80, the native ligand to the heme iron, is replaced by a Lys. While it has become clear that the structure of cyt c changes, the extent and sequence of conformational rearrangements associated with this ligand replacement remain a subject of debate. Herein we report a high-resolution crystal structure of a Lys73-ligated cyt c conformation that reveals intricate change in the heme environment upon this switch in the heme iron ligation. The structure is surprisingly compact, and the heme coordination loop refolds into a β-hairpin with a turn formed by the highly conserved residues Pro76 and Gly77. Repositioning of residue 78 modifies the intraprotein hydrogen-bonding network and, together with adjustments of residues 52 and 74, increases the volume of the heme pocket to allow for insertion of one of the CL acyl moieties next to Asn52. Derivatization of Cys78 with maleimide creates a solution mimic of the Lys-ligated cyt c that has enhanced peroxidase activity, adding support for a role of the Lys-ligated cyt c in the apoptotic mechanism. Experiments with the heme peptide microperoxidase-8 and engineered model proteins provide a thermodynamic rationale for the switch to Lys ligation upon perturbations in the protein scaffold.

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Section: Discussionmentioning

confidence: 96%

A Compact Structure of Cytochrome c Trapped in a Lysine-Ligated State: Loop Refolding and Functional Implications of a Conformational Switch

et al. 2015

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“…This ferrous state of pentacoordinated cyt c predisposes the oxidation of Met 80 to Met 80 -O [38], and inhibits the re-ligation of Met 80 to heme Fe [39, 40]. The reduction potential of pentacoordinated cyt c is significantly lower than native cyt c , and this inhibits the reduction of cyt c by complex III in the ETC [15, 16]. These changes can account for the inhibition of mitochondrial respiration when ischemic mitochondria are exposed to reperfusion conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Cardiolipin is known to inhibit the reduction of cyt c [13–15]. Cyt c (20 μM) was preincubated with CL, in the absence or presence of different concentrations of SS-20, for 1 min.…”

Section: Methodsmentioning

confidence: 99%

“…Electrostatic interaction between cyt c and CL anchors cyt c to the IMM and optimizes ET between complex III and complex IV [13]. Interestingly, low ATP conditions favor hydrophobic interaction between cyt c and CL [14, 15], which is known to disrupt the Met 80 -Fe ligation, resulting in a pentacoordinated heme Fe [16–19]. The loss of the Met 80 -Fe ligation inhibits ET and converts cyt c from an electron carrier to an oxygenase/peroxidase that can cause CL peroxidation [12, 20–23].…”

Section: Introductionmentioning

confidence: 99%

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Disruption of cytochrome c heme coordination is responsible for mitochondrial injury during ischemia

Birk

Chao

Liu

et al. 2015

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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Background It was recently suggested that electron flow into cyt c, coupled with ROS generation, oxidizes cyt c Met80 to Met80 sulfoxide (Met-O) in isolated hearts after ischemia-reperfusion, and converts cyt c to a peroxidase. We hypothesize that ischemia disrupts Met80-Fe ligation of cyt c, forming pentacoordinated heme Fe2+, which inhibits electron transport (ET) and promotes oxygenase activity. Methods SS-20 (Phe-D-Arg-Phe-Lys-NH2) was used to demonstrate the role of Met80-Fe ligation in ischemia. Mitochondria were isolated from ischemic rat kidneys to determine sites of respiratory inhibition. Mitochondrial cyt c and cyt c Met-O were quantified by western blot, and cristae architecture was examined by electron microscopy. Results Biochemical and structural studies showed that SS-20 selectively targets cardiolipin (CL) and protects Met80-Fe ligation in cyt c. Ischemic mitochondria showed 17-fold increase in Met-O cyt c, and dramatic cristaeolysis. Loss of cyt c was associated with proteolytic degradation of OPA1. Ischemia significantly inhibited ET initiated by direct reduction of cyt c and coupled respiration. All changes were prevented by SS-20. Conclusion Our results show that ischemia disrupts the Met80-Fe ligation of cyt c resulting in formation of a globin-like pentacoordinated heme Fe2+ that inhibits ET, and converts cyt c into an oxygenase to cause CL peroxidation and proteolytic degradation of OPA1, resulting in cyt c release. General significance Cyt c heme structure represents a novel target for minimizing ischemic injury. SS-20, which we show to selectively target CL and protect the Met80-Fe ligation, minimizes ischemic injury and promotes ATP recovery.

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“…Pletneva and coworkers have recently applied their FRET technique to study ferricytochrome c on liposomes with different CL contents [170][171][172][173]. As observed for unfolded or partially unfolded cytochrome in solution, they identified an equilibrium between compact and extended states.…”

Section: Unfolding Of Cytochrome C On Anionic Liposome Surfacesmentioning

confidence: 99%

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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Multifaceted Effects of ATP on Cardiolipin-Bound Cytochrome c

Cited by 25 publications

References 27 publications

A Compact Structure of Cytochrome c Trapped in a Lysine-Ligated State: Loop Refolding and Functional Implications of a Conformational Switch

A Compact Structure of Cytochrome c Trapped in a Lysine-Ligated State: Loop Refolding and Functional Implications of a Conformational Switch

Disruption of cytochrome c heme coordination is responsible for mitochondrial injury during ischemia

Cytochrome c: A Multifunctional Protein Combining Conformational Rigidity with Flexibility

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