The Bax pore in liposomes, Biophysics

Schlesinger, Paul H.; Saito, Mitsuyoshi

doi:10.1038/sj.cdd.4401991

Cited by 32 publications

(22 citation statements)

References 77 publications

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“…For example, during apoptosis, Bax expression is upregulated 16,17 and its structure is activated, 18 which results in its migration toward the mitochondrial outer membrane (MOM). 19 Afterward, Bax is inserted in the MOM and is capable of making oligomers 2,20,21 to permeabilize the MOM. 22 The three-dimensional (3D) structure of Bax has been determined by nuclear magnetic resonance, identifying nine alpha helices (aH1-9), joined by loops (Lp1-2, Lp2-3, Lp3-4, Lp4-5, Lp5-6, Lp6-7, Lp7-8, and Lp8-9) with some turns.…”

Section: Introductionmentioning

confidence: 99%

Insights into the structural stability of Bax from molecular dynamics simulations at high temperatures

Rosas-Trigueros¹,

Correa‐Basurto²,

Benítez‐Cardoza³

et al. 2011

Protein Science

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Bax is a member of the Bcl-2 protein family that participates in mitochondrion-mediated apoptosis. In the early stages of the apoptotic pathway, this protein migrates from the cytosol to the outer mitochondrial membrane, where it is inserted and usually oligomerizes, making cytochrome c-compatible pores. Although several cellular and structural studies have been reported, a description of the stability of Bax at the molecular level remains elusive. This article reports molecular dynamics simulations of monomeric Bax at 300, 400, and 500 K, focusing on the most relevant structural changes and relating them to biological experimental results. Bax gradually loses its a-helices when it is submitted to high temperatures, yet it maintains its globular conformation. The resistance of Bax to adopt an extended conformation could be due to several interactions that were found to be responsible for maintaining the structural stability of this protein. Among these interactions, we found salt bridges, hydrophobic interactions, and hydrogen bonds. Remarkably, salt bridges were the most relevant to prevent the elongation of the structure. In addition, the analysis of our results suggests which conformational movements are implicated in the activation/oligomerization of Bax. This atomistic description might have important implications for understanding the functionality and stability of Bax in vitro as well as within the cellular environment.

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Section: Introductionmentioning

confidence: 99%

Insights into the structural stability of Bax from molecular dynamics simulations at high temperatures

Rosas-Trigueros¹,

Correa‐Basurto²,

Benítez‐Cardoza³

et al. 2011

Protein Science

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“…The progressive effect could also be due to continued equilibration of Bax out of the mitoplasts matrix space to the channel through the narrow neck of the Ω-shaped patch even after washout has eliminated Bax from the bath side. We found no indication that Bax itself could have channel properties [27][28][29]. No additional ion channels with a different fingerprint (i.e., γ, P o , kinetics), either in RLM or in astrocyte mitoplasts, were found to open after application of proteins from the Bcl-2 family.…”

Section: Discussionmentioning

confidence: 75%

“…Thus, it seems that the channel properties which have been predicted by the structure of e.g. Bax [28] are Bax Modulates PTP via mtBK Channel Fig. 8.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Permeability Transition Pore by Bax via Inhibition of the Mitochondrial BK Channel

Cheng

Gulbins

Siemen

2011

Cell Physiol Biochem

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Mitochondria are crucially involved in the intrinsic pathway of apoptosis. Upon induction of apoptosis, proapoptotic proteins of the Bcl-2 family, in particular Bax and Bak, transfer the death signal to the organelle. The outcome is release of proapoptotic factors, such as cytochrome c, and mitochondrial changes, such as depolarization. Details of the mechanism by which Bax mediates mitochondrial alterations, however, are unknown. Using the single-channel patch-clamp method, we studied mitoplasts (vesicles of inner membrane) from rat astrocyte and liver mitochondria and intact murine glioma mitochondria to determine the action of proapoptotic Bax and antiapoptotic Bcl-xL on the mitochondrial Ca²⁺-activated channel (mtBK) and the permeability transition pore (mtPTP). Bax (1 nM) inhibited the open probability of the mtBK, whereas Bcl-xL or control proteins had no effect. Incubating mitochondria with iberiotoxin, an inhibitor of mtBK, induced the release of cytochrome c. Bcl-xL inhibited the effects of Bax on mtBK. Furthermore, in patch-clamp studies Bcl-xL inhibited the mtPTP itself, whereas Bax had no direct effect on the mtPTP. We conclude that Bax exerts its proapototic effect by inhibiting mitochondrial K⁺ channels, whereas Bcl-xL exerts its antiapoptotic effect by inhibiting the effects of Bax on mitochondrial potassium channels and by direct inhibition of the mtPTP.

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“…We have used the analysis of dequenching to study the activation of pores in bilayer membranes [83,84,85,19]. Using mono-disperse unilamellar vesicles the activation of membrane pores was studied by measurement of the increased fluorescence as carboxyfluorescein exits from the membrane compartment and is diluted into the assay volume.…”

Section: Dequenching Analysis Of Bax Pore Activationmentioning

confidence: 99%

Cholesterol Effects on BAX Pore Activation

Christenson

Merlin

Saito

et al. 2008

Journal of Molecular Biology

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The importance of BCL-2-family proteins in the control of cell death has been clearly established. One of the key members of this family, BAX, has soluble, membrane bound and membrane integrated forms that are central to the regulation of apoptosis. Using purified monomeric human BAX, defined liposomes and isolated human mitochondria we have characterized the soluble to membrane transition and pore formation by this protein. For the purified protein, activation but not oligomerization, is required for membrane binding. The transition to the membrane environment includes a binding step that is reversible and distinct from the membrane integration step. Oligomerization and pore activation occur after the membrane integration. In cells, BAX targets several intracellular membranes, but notably does not target the plasma membrane while initiating apoptosis. When cholesterol was added to either the liposome bilayer or mitochondrial membranes we observed increased binding but markedly reduced integration of BAX into both membranes. This cholesterol inhibition of membrane integration accounts for the reduction of BAX pore activation in liposomes and mitochondrial membranes. Our results indicate that the presence of cholesterol in membranes inhibits the pore forming activity of BAX by reducing the ability of BAX to transition from a membrane associated to a membrane integral protein.

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The Bax pore in liposomes, Biophysics

Cited by 32 publications

References 77 publications

Insights into the structural stability of Bax from molecular dynamics simulations at high temperatures

Insights into the structural stability of Bax from molecular dynamics simulations at high temperatures

Activation of the Permeability Transition Pore by Bax via Inhibition of the Mitochondrial BK Channel

Cholesterol Effects on BAX Pore Activation

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