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Binding of S. cerevisiae iso-1 cytochrome c and its surface lysine-to-alanine variants to cardiolipin: charge effects and the role of the lipid to protein ratio

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Abstract

The interaction of cytochrome c with cardiolipin (CL) is a critical step in the initial stages of apoptosis and is mediated by a positively charged region on the protein surface comprising several lysine residues (site A). Here, the interaction of wt S. cerevisiae cytochrome c (ycc) and its K72A/K73A, K72A/K79A, K73A/K79A and K72A/K73A/K79A variants with CL was studied through UV–Vis and MCD spectroscopies at pH 7 and molecular dynamics (MD) simulations, to clarify the role of the mutated lysines. Moreover, the influence of the lipid to protein ratio on the interaction mechanism was investigated using low (0.5–10) and high (5–60) CL/ycc molar ratios, obtained with small and gradual or large and abrupt CL additions, respectively. Although all proteins bind to CL, switching from the native low-spin His/Met-ligated form to a low-spin bis-His conformer and to a high-spin species at larger CL concentrations, the two schemes of CL addition show relevant differences in the CL/ycc molar ratios at which the various conformers appear, due to differences in the interaction mechanism. Extended lipid anchorage and peripheral binding appear to prevail at low and high CL/ycc molar ratios, respectively. Simultaneous deletion of two or three surface positive charges from Site A does not abolish CL binding, but instead increases protein affinity for CL. MD calculations suggest this unexpected behavior results from the mutation-induced severe weakening of the H-bond connecting the Nε of His26 with the backbone oxygen of Glu44, which lowers the conformational stability compared to the wt species, overcoming the decreased surface electrostatic interaction.

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Funding

This work was supported by the University of Modena and Reggio Emilia FAR 2016 and FAR 2019 funding programs.

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Authors and Affiliations

  1. Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK

    Alessandro Paradisi

  2. Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41126, Modena, Italy

    Marzia Bellei, Carlo Augusto Bortolotti, Giulia Di Rocco, Antonio Ranieri & Marco Sola

  3. Department of Chemistry and Geology, University of Modena and Reggio Emilia, Via Campi 103, 41126, Modena, Italy

    Licia Paltrinieri, Marco Borsari & Gianantonio Battistuzzi

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  1. Alessandro Paradisi
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Paradisi, A., Bellei, M., Paltrinieri, L. et al. Binding of S. cerevisiae iso-1 cytochrome c and its surface lysine-to-alanine variants to cardiolipin: charge effects and the role of the lipid to protein ratio. J Biol Inorg Chem 25, 467–487 (2020). https://doi.org/10.1007/s00775-020-01776-1

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