Ceramide Channels and the Induction of Apoptosis: Structural Insights on Channel Formation and Regulation by Bcl-2 Family Proteins
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چکیده
Title of Dissertation: CERAMIDE CHANNELS AND THE INDUCTION OF APOPTOSIS: STRUCTURAL INSIGHTS ON CHANNEL FORMATION AND REGULATION BY BCL-2 FAMILY PROTEINS. Meenu Nadisha Perera, Doctor of Philosophy, 2012 Directed by: Professor Marco Colombini Department of Biology A critical event in apoptosis is the release of intermembrane space proteins from mitochondria following mitochondrial outer membrane (MOM) permeabilization (MOMP). The Bcl-2 family of proteins regulates MOM integrity and includes proand anti-apoptotic members, like Bax and Bcl-xL respectively. Preceding MOMP, the MOM becomes enriched with the sphingolipid, ceramide, which can self-assemble to form ceramide channels, contributing to MOMP. Bax and ceramide channels were found to act synergistically in the generation of MOMP and a direct interaction between these was observed in phospholipid membranes. The apparent affinity of activated Bax for ceramide channels increases with ceramide channel size, consistent with an induced fit mechanism; Bax drives the enlargement of ceramide channels to an optimum fit for the Bax binding site. A ceramide channel specific inhibitor prevented the enhanced MOMP in the presence of Bax and ceramide indicating ceramide channels were the primary permeabilizing entity.
منابع مشابه
Regulation of ceramide channels by Bcl-2 family proteins.
Mitochondrial outer membrane permeabilization to proteins, an irreversible step in apoptosis by which critical proteins are released, is tightly regulated by Bcl-2 family proteins. The exact nature of the release pathway is still undefined. Ceramide is an important sphingolipid, involved in various cellular processes including apoptosis. Here we describe the structural properties of ceramide ch...
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The present study demonstrates the important structural features of ceramide required for proper regulation, binding and identification by both pro-apoptotic and anti-apoptotic Bcl-2 family proteins. The C-4=C-5 trans-double bond has little influence on the ability of Bax and Bcl-xL to identify and bind to these channels. The stereochemistry of the headgroup and access to the amide group of cer...
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Early in mitochondria-mediated apoptosis, the mitochondrial outer membrane becomes permeable to proteins that, when released into the cytosol, initiate the execution phase of apoptosis. Proteins in the Bcl-2 family regulate this permeabilization, but the molecular composition of the mitochondrial outer membrane pore is under debate. We reported previously that at physiologically relevant levels...
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A key, decision-making step in apoptosis is the release of proteins from the mitochondrial intermembrane space. Ceramide can self-assemble in the mitochondrial outer membrane to form large stable channels capable of releasing said proteins. Ceramide levels measured in mitochondria early in apoptosis are sufficient to form ceramide channels in the outer membrane. The channels are in dynamic equi...
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