title: Peptides derived from the transmembrane domain of Bcl-2 proteins as potential mitochondrial priming tools.
abstract: 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-protein 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.
authors.affiliation: Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe , E-46012 Valencia, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Andreu-Fernández
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Genoves
authors.forename: Tzong-Hsien
authors.initials: TH
authors.lastname: Lee
authors.forename: Matthew
authors.initials: M
authors.lastname: Stellato
authors.forename: Federico
authors.initials: F
authors.lastname: Lucantoni
authors.forename: Mar
authors.initials: M
authors.lastname: Orzáez
authors.forename: Ismael
authors.initials: I
authors.lastname: Mingarro
authors.forename: Marie-Isabel
authors.initials: MI
authors.lastname: Aguilar
authors.forename: Enrique
authors.initials: E
authors.lastname: Pérez-Payá
mesh_terms: D000595:Amino Acid Sequence; D019070:Cell Lineage; D002942:Circular Dichroism; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry*
chemical_list: D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2