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First published online 31 July 2007
doi: 10.1242/jcs.006197

Journal of Cell Science 120, 2912-2923 (2007)
Published by The Company of Biologists 2007
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Research Article

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

Jae-Kyun Ko1, Kyoung-Han Choi1, Zui Pan1, Peihui Lin1, Noah Weisleder1, Chul-Woo Kim2 and Jianjie Ma1,*

1 Department of Physiology and Biophysics, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA
2 Department of Pathology, Tumor Immunity Medical Research Center and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

* Author for correspondence (e-mail: maj2{at}umdnj.edu)

Accepted 13 June 2007

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.

Key words: ATAP, Bfl1, Apoptosis, Tail anchor


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