Peptides Derived from the Transmembrane Domain of Bcl-2 Proteins as Potential Mitochondrial Priming Tools

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• 作者：Vicente Andreu-Fern谩ndez ; Ainhoa Genoves ; Tzong-Hsien Lee ; Matthew Stellato ; Federico Lucantoni ; Mar Orz谩ez ; Ismael Mingarro ; Marie-Isabel Aguilar ; Enrique P茅rez-Pay谩
• 刊名：ACS Chemical Biology
• 出版年：2014
• 出版时间：August 15, 2014
• 年：2014
• 卷：9
• 期：8
• 页码：1799-1811
• 全文大小：779K
• ISSN：1554-8937

文摘

The Bcl-2 family of proteins is crucial for apoptosis regulation. Members of this family insert through a specific C-terminal anchoring transmembrane domain (TMD) in the mitochondrial outer membrane where they hierarchically interact to determine cell fate. While the mitochondrial membrane has been proposed to actively participate in these protein鈥損rotein interactions, the influence of the TMD in the membrane-mediated interaction is poorly understood. Synthetic peptides (TMD-pepts) corresponding to the putative TMD of antiapoptotic (Bcl-2, Bcl-xL, Bcl-w, and Mcl-1) and pro-apoptotic (Bax, Bak) members were synthesized and characterized. TMD-pepts bound more efficiently to mitochondria-like bilayers than to plasma membrane-like bilayers, and higher binding correlated with greater membrane perturbation. The Bcl-2 TMD peptides promoted mitochondrial outer membrane permeabilization (MOMP) and cytochrome c release from isolated mitochondria and different cell lines. TMD-pepts exhibited nonapoptotic pro-death activity when apoptosis stimuli were absent. In addition, the peptides enhanced the apoptotic pathway induced by chemotherapeutic agents in cotreatment. Overall, the membrane perturbation effects of the TMD-pepts observed in the present study open the way for their use as new chemical tools to sensitize tumor cells to chemotherapeutic agents, in accordance with the concept of mitochondria priming.