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The tail-anchoring domain of Bfl1 and HCCS1 targets mitochondrial membrane permeability to induce apoptosis

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Authors
Ko, Jae-Kyun; Choi, Kyoung-Han; Pan, Zui; Lin, Peihui; Weisleder, Noah; Kim, Chul-Woo; Ma, Jianjie
Issue Date
2007-08-02
Publisher
Company of Biologists
Citation
J. Cell Sci. 120(Pt 16), 2912-2923
Keywords
Amino Acid Sequence*ApoptosisBase SequenceCell Line, TumorConserved SequenceLipid Bilayers/metabolismMembrane Potential, MitochondrialMitochondrial Membranes/*metabolismMolecular Sequence DataPeptides/chemistryPermeabilityProtein Sorting SignalsProtein Structure, TertiaryProtein TransportProto-Oncogene Proteins c-bcl-2/*chemistry/genetics/*metabolismStructure-Activity RelationshipTumor Suppressor Proteins/*chemistry/genetics/*metabolismbcl-2 Homologous Antagonist-Killer Protein/metabolismbcl-2-Associated X Protein/metabolism
Abstract
Many Bcl2 family proteins target intracellular membranes by their C-terminal tail-anchor domain. Bfl1 is a bi-functional Bcl2 family protein with both anti- and pro-apoptotic activities and contains an amphipathic tail-anchoring peptide (ATAP; residues 147-175) with unique properties. Here we show that ATAP targets specifically to mitochondria, and induces caspase-dependent apoptosis that does not require Bax or Bak. Mutagenesis studies revealed that lysine residues flanking the ATAP sequence are involved in targeting of the peptide to the mitochondrial membrane, and charged residues that contribute to the amphipathic nature of ATAP are critical for its pro-apoptotic function. The ATAP sequence is present in another tumor suppressor gene, HCCS1, which contains an additional mitochondria-targeting signal (MTS) close to the ATAP. We propose that both ATAP and MTS could be used as therapeutic peptides to induce cell death in the treatment of cancer cells.
ISSN
0021-9533 (Print)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17666431

http://hdl.handle.net/10371/10013
DOI
https://doi.org/10.1242/jcs.006197
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College of Medicine/School of Medicine (의과대학/대학원)Pathology (병리학전공)Journal Papers (저널논문_병리학전공)
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