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

Li, Mingyue; Mandal, Arabinda; Tyurin, Vladimir A.; DeLucia, Maria; Ahn, Jin-Woo; Kagan, Valerian E.; Wel, Patrick C.A. van der

doi:10.1016/j.str.2019.02.007

Cited by 30 publications

(41 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1c) [38]. Thus, both CL and PG feature saturating stoichiometries at approximately twelve negative charges, in a nanodomain with a similar surface area, which in turn matches the footprint of (folded) cyt c [51]. These findings support the common notion that a peripheral interaction between cyt c and anionic lipids can be seen as dominated by electrostatic forces [43,53].…”

Section: Stoichiometry Of the Protein-lipid Complexsupporting

confidence: 57%

Activation of Cytochrome C Peroxidase Function Through Coordinated Foldon Loop Dynamics upon Interaction with Anionic Lipids

Sun

Tyurin

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Cardiolipin (CL) is a mitochondrial anionic lipid that plays important roles in the regulation and signaling of mitochondrial apoptosis. CL peroxidation catalyzed by the assembly of CL-cytochrome c (cyt c) complexes at the inner mitochondrial membrane is a critical checkpoint. The structural changes in the protein, associated with peroxidase activation by CL and different anionic lipids, are not known at a molecular level. To better understand these peripheral protein-lipid interactions, we compare how phosphatidylglycerol (PG) and CL lipids trigger cyt c peroxidase activation, and correlate functional differences to structural and motional changes in membrane-associated cyt c. Structural and motional studies of the bound protein are enabled by magic angle spinning solid state NMR spectroscopy, while lipid peroxidase activity is assayed by mass spectrometry. PG binding results in a surface-bound state that preserves a nativelike fold, which nonetheless allows for significant peroxidase activity, though at a lower level than binding its native substrate CL. Lipid-specific differences in peroxidase activation are found to correlate to corresponding differences in lipid-induced protein mobility, affecting specific protein segments. The dynamics of omega loops C and D are upregulated by CL binding, in a way that is remarkably controlled by the protein:lipid stoichiometry. In contrast to complete chemical denaturation, membrane-induced protein destabilization reflects a destabilization of select cyt c foldons, while the energetically most stable helices are preserved. Our studies illuminate the interplay of protein and lipid dynamics in the creation of lipid peroxidase-active proteolipid complexes implicated in early stages of mitochondrial apoptosis.

show abstract

Section: Stoichiometry Of the Protein-lipid Complexsupporting

confidence: 57%

Activation of Cytochrome C Peroxidase Function Through Coordinated Foldon Loop Dynamics upon Interaction with Anionic Lipids

Sun

Tyurin

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…These elements support the concept that CL potentially creates a unique environment for BCL2 family proteins and promotes mitochondrial membrane alterations that facilitate bilayer structure remodeling, deformation, and ultimately permeabilization. Moreover, the peroxidized isoform of CL (CLox) weakens the interaction of cytochrome c with the MIM, a process that may also contribute to ease MOMP [82,89,90].…”

Section: Perspective In Bcl2 Universementioning

confidence: 99%

The Incomplete Puzzle of the BCL2 Proteins

Flores‐Romero

García‐Sáez

2019

Cells

View full text Add to dashboard Cite

The proteins of the BCL2 family are key players in multiple cellular processes, chief amongst them being the regulation of mitochondrial integrity and apoptotic cell death. These proteins establish an intricate interaction network that expands both the cytosol and the surface of organelles to dictate the cell fate. The complexity and unpredictability of the BCL2 interactome resides in the large number of family members and of interaction surfaces, as well as on their different behaviours in solution and in the membrane. Although our current structural knowledge of the BCL2 proteins has been proven therapeutically relevant, the precise structure of membrane-bound complexes and the regulatory effect that membrane lipids exert over these proteins remain key questions in the field. Here, we discuss the complexity of BCL2 interactome, the new insights, and the black matter in the field.

show abstract

“…1,4,28,30,41 The paradigm of this tunable functionality in vivo is the interaction with cardiolipin (CL), a negatively charged glycerophospholipid found in the inner mitochondrial membrane (IMM), 30,40,42 which induces the cleavage of the Fe-S(Met80) bond, 1,5,9,19,21,28,30,32,39, imparting to cytc significant (lipo)peroxidase activity, which is crucial in triggering the apoptosis cascade. 1,5,28,30,40,47,73 In vitro, analogous heme axial ligand swapping from His/Met to His/His occurs upon chemical denaturation of both solution 14 and surface-immobilized yeast cytochrome c (ycc). 14,33,34,[74][75][76][77] Under the latter conditions, ycc gains remarkable pseudo-peroxidase activity.…”

Section: Introductionmentioning

confidence: 99%

Met80 and Tyr67 affect the chemical unfolding of yeast cytochromec: comparing the solutionvs.immobilized state

et al. 2020

View full text Add to dashboard Cite

show abstract

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

Abstract: Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Cited by 30 publications

References 70 publications

Activation of Cytochrome C Peroxidase Function Through Coordinated Foldon Loop Dynamics upon Interaction with Anionic Lipids

Activation of Cytochrome C Peroxidase Function Through Coordinated Foldon Loop Dynamics upon Interaction with Anionic Lipids

The Incomplete Puzzle of the BCL2 Proteins

Met80 and Tyr67 affect the chemical unfolding of yeast cytochromec: comparing the solutionvs.immobilized state

Contact Info

Product

Resources

About