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

Abstract

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.

Surface-Binding to Cardiolipin Nanodomains Triggers Cytochrome c Pro-apoptotic Peroxidase Activity via Localized Dynamics

“…The structural changes in cyt c caused by binding to CL-containing membrane that facilitate its ondemand lipid peroxidase activity, remain elusive. As delineated in a recent comprehensive review (Schweitzer-Stenner, 2018), one challenge relates to the fact that the CL-cyt c interaction is modulated strongly by experimental context. There is also a lack of techniques to probe membrane-bound cyt c with atomic resolution.…”

“…In solution NMR studies, the membrane-bound protein tumbles too slowly to be observable, even though changes in the spectra of soluble protein reveal aspects of the initial membrane interactions (Brown and Wuthrich, 1977;Kobayashi et al, 2016;Mohammadyani et al, 2018). As such, current insight into membrane-bound cyt c is derived from diverse complementary lower-resolution techniques (Schweitzer-Stenner, 2018). These suggest that cyt c can interact with CL via multiple binding sites (Alvarez-Paggi et al, 2017;Schweitzer-Stenner, 2018).…”

“…As such, current insight into membrane-bound cyt c is derived from diverse complementary lower-resolution techniques (Schweitzer-Stenner, 2018). These suggest that cyt c can interact with CL via multiple binding sites (Alvarez-Paggi et al, 2017;Schweitzer-Stenner, 2018). Most prominent is the so-called "site A", featuring lysines K72, K73, K86, and K87, which would facilitate an electrostatic interaction with the negatively charged CL (Rytomaa and Kinnunen, 1994;Sinibaldi et al, 2017).…”

“…Protein unfolding is known to induce high peroxidase activity in cyt c, and has been reported to occur upon membrane binding. The impact of membrane binding is highly dependent on sample conditions (Schweitzer-Stenner, 2018). Several prior studies have highlighted the importance of the effective CL/cyt c ratio.…”

New moonlighting functions of mitochondrial cytochrome c in the cytoplasm and nucleus

“…It is believed that C c is partially unfolded when bound to mitochondrial negatively charged phospholipids, including cardiolipin, which confers peroxidase activity on the metalloprotein . Interestingly, at early stages of apoptosis, cardiolipin‐bound C c selectively catalyzes cardiolipin peroxidation, which contributes to the OMM permeation and leads to the release of C c into the cytosol . Accordingly, it has been suggested that the apoptosis‐inducing form of C c is the membrane‐bound fraction .…”