The tail-anchoring domain of Bfl1 and HCCS1 targets mitochondrial membrane permeability to induce apoptosis.
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.
Department of Physiology and Biophysics, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA.
Jae-Kyun
JK
Ko
Kyoung-Han
KH
Choi
Zui
Z
Pan
Peihui
P
Lin
Noah
N
Weisleder
Chul-Woo
CW
Kim
Jianjie
J
Ma
D000595:Amino Acid Sequence; D017209:Apoptosis; D001483:Base Sequence; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D015778:Minor Histocompatibility Antigens; D051336:Mitochondrial Membranes / Q000378:metabolism*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D010539:Permeability; D021382:Protein Sorting Signals; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C096816:BCL2-related protein A1; D008051:Lipid Bilayers; D015778:Minor Histocompatibility Antigens; D010455:Peptides; D021382:Protein Sorting Signals; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; C503307:VPS53 protein, human; D033921:Vesicular Transport Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein