2015
DOI: 10.1186/s13062-015-0059-4
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Modeling of interaction between cytochrome c and the WD domains of Apaf-1: bifurcated salt bridges underlying apoptosome assembly

Abstract: BackgroundBinding of cytochrome c, released from the damaged mitochondria, to the apoptotic protease activating factor 1 (Apaf-1) is a key event in the apoptotic signaling cascade. The binding triggers a major domain rearrangement in Apaf-1, which leads to oligomerization of Apaf-1/cytochrome c complexes into an apoptosome. Despite the availability of crystal structures of cytochrome c and Apaf-1 and cryo-electron microscopy models of the entire apoptosome, the binding mode of cytochrome c to Apaf-1, as well a… Show more

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Cited by 16 publications
(15 citation statements)
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“…This has been highlighted recently through the discovery of a species-dependent interaction between cyt and Apaf-1 in cytosolic extracts, which is proposed to arise due to sequence variation between mitochondrial species in the 40–57 Ω-loop 45 . Further to this discovery, residues flanking Pro44 have for some time been associated with a conformational change in cells undergoing apoptosis 46 and recent modelling studies suggest H-cyt interacts with Apaf-1 through contact via the 40–57 Ω-loop 45 47 . Thus based on the present work we propose that the dynamics of 40–57 Ω-loop may be species-specific and tuned to regulate interaction with the cognate Apaf-1.…”
Section: Resultsmentioning
confidence: 98%
“…This has been highlighted recently through the discovery of a species-dependent interaction between cyt and Apaf-1 in cytosolic extracts, which is proposed to arise due to sequence variation between mitochondrial species in the 40–57 Ω-loop 45 . Further to this discovery, residues flanking Pro44 have for some time been associated with a conformational change in cells undergoing apoptosis 46 and recent modelling studies suggest H-cyt interacts with Apaf-1 through contact via the 40–57 Ω-loop 45 47 . Thus based on the present work we propose that the dynamics of 40–57 Ω-loop may be species-specific and tuned to regulate interaction with the cognate Apaf-1.…”
Section: Resultsmentioning
confidence: 98%
“…Opa1 is well known for its role in the regulation of mitochondrial dynamics, where it inhibits mitochondrial cristae remodeling and cytochrome c release (13,51). cytochrome c released into the cytosol can recruit pro-apoptotic signals and trigger downstream apoptotic events by binding between the two tryptophan (W) and aspartate (d)-rich Wd domains of the apoptotic protease activating factor (Apaf-1), thereby irreversibly activating the apoptotic cascade (52). cristae morphogenesis, which is induced by the reduction of Opa1 expression, may increase the probability of cytochrome c release (53,54).…”
Section: Discussionmentioning
confidence: 99%
“…This binding causes a major conformational change that eventually could lead to the assembly of apoptosome. Molecular modeling predicted that cytochrome c binds owing to the interaction of its lysine residues with conserved Asp residues of Apaf-1 (Shalaeva et al, 2015). The recently resolved apoptosome structure confirmed the involvement of conserved Asp residues in cytochrome c binding (Zhou et al, 2015).…”
Section: Discussionmentioning
confidence: 99%