Characterization of the signal that directs Bcl-x(L), but not Bcl-2, to the mitochondrial outer membrane - PubMed (original) (raw)
Characterization of the signal that directs Bcl-x(L), but not Bcl-2, to the mitochondrial outer membrane
Thomas Kaufmann et al. J Cell Biol. 2003.
Abstract
It is assumed that the survival factors Bcl-2 and Bcl-x(L) are mainly functional on mitochondria and therefore must contain mitochondrial targeting sequences. Here we show, however, that only Bcl-x(L) is specifically targeted to the mitochondrial outer membrane (MOM) whereas Bcl-2 distributes on several intracellular membranes. Mitochondrial targeting of Bcl-x(L) requires the COOH-terminal transmembrane (TM) domain flanked at both ends by at least two basic amino acids. This sequence is a bona fide targeting signal for the MOM as it confers specific mitochondrial localization to soluble EGFP. The signal is present in numerous proteins known to be directed to the MOM. Bcl-2 lacks the signal and therefore localizes to several intracellular membranes. The COOH-terminal region of Bcl-2 can be converted into a targeting signal for the MOM by increasing the basicity surrounding its TM. These data define a new targeting sequence for the MOM and propose that Bcl-2 acts on several intracellular membranes whereas Bcl-x(L) specifically functions on the MOM.
Figures
Figure 1.
Bcl-xL and Bcl-xS specifically localize to the MOM, whereas Bcl-2 resides on several membranes. (A) Anti–Bcl-2 and anti–Bcl-x Western blots of subcellular fractions from parental HEK 293 cells (endo) or HEK293 cells transiently overexpressing Bcl-2, Bcl-xL, or FLAG–Bcl-xS (exo). The mitochondrial fraction was obtained from the 1.4 M band and the heavy microsomal fraction from the 1.0 M band of the sucrose gradient (see Materials and methods). Light microsomes are the pellet of the 100,000 g spin. Purity of the fractions was checked with anti-grp78/Bip and anti-KDEL (microsomes) and anti–COX-VIc (mitochondria) antibodies. TAP(I-VI)–EGFP contains the first six membrane-spanning regions of the antigen peptide transporter I (TAP I) fused to EGFP. This protein specifically spans the ER membrane and is detected by anti-GFP Western blotting after transient transfection. (B) Anti–Bcl-x Western blots of mitochondrial matrix, inner membrane (mb), and outer membrane fractions of rat liver, HEK293 cells, and HEK293 cells transiently overexpressing Bcl-xL (HEK293/Bcl-xL). (C) Anti–Bcl-2 and anti–Bcl-x Western blots of mitochondria or microsomes from parental HEK293 cells or HEK293 cells overexpressing Bcl-2 or Bcl-xL or FLAG–Bcl-xS, extracted directly with detergent (total) or first treated with sodium carbonate (pH 12, peripheral) and then extracted with detergent (integral). (D) Autoradiography of [35S]methionine-labeled, in vitro–transcribed/translated (IVTT) Bcl-2, Bcl-xL, or FLAG–Bcl-xS inserted (alkali resistant, integral) or loosely attached (alkali extractable, peripheral) to mitochondria or microsomes (pellet), or remaining in the supernatant after spinning off the organelles. (E) Anti–Bcl-2 and anti–Bcl-x immunofluorescence analysis of R6 cells transiently overexpressing Bcl-xL, FLAG-Bcl-xS, or Bcl-2 (green). Whereas both Bcl-xL and FLAG–Bcl-xS colocalize with the mitochondrial marker cytochrome c (Cyt.c, red), Bcl-2 colocalizes with the ER marker calnexin (red). Nuclei were stained with Hoechst 33342 (blue in the merge).
Figure 1.
Bcl-xL and Bcl-xS specifically localize to the MOM, whereas Bcl-2 resides on several membranes. (A) Anti–Bcl-2 and anti–Bcl-x Western blots of subcellular fractions from parental HEK 293 cells (endo) or HEK293 cells transiently overexpressing Bcl-2, Bcl-xL, or FLAG–Bcl-xS (exo). The mitochondrial fraction was obtained from the 1.4 M band and the heavy microsomal fraction from the 1.0 M band of the sucrose gradient (see Materials and methods). Light microsomes are the pellet of the 100,000 g spin. Purity of the fractions was checked with anti-grp78/Bip and anti-KDEL (microsomes) and anti–COX-VIc (mitochondria) antibodies. TAP(I-VI)–EGFP contains the first six membrane-spanning regions of the antigen peptide transporter I (TAP I) fused to EGFP. This protein specifically spans the ER membrane and is detected by anti-GFP Western blotting after transient transfection. (B) Anti–Bcl-x Western blots of mitochondrial matrix, inner membrane (mb), and outer membrane fractions of rat liver, HEK293 cells, and HEK293 cells transiently overexpressing Bcl-xL (HEK293/Bcl-xL). (C) Anti–Bcl-2 and anti–Bcl-x Western blots of mitochondria or microsomes from parental HEK293 cells or HEK293 cells overexpressing Bcl-2 or Bcl-xL or FLAG–Bcl-xS, extracted directly with detergent (total) or first treated with sodium carbonate (pH 12, peripheral) and then extracted with detergent (integral). (D) Autoradiography of [35S]methionine-labeled, in vitro–transcribed/translated (IVTT) Bcl-2, Bcl-xL, or FLAG–Bcl-xS inserted (alkali resistant, integral) or loosely attached (alkali extractable, peripheral) to mitochondria or microsomes (pellet), or remaining in the supernatant after spinning off the organelles. (E) Anti–Bcl-2 and anti–Bcl-x immunofluorescence analysis of R6 cells transiently overexpressing Bcl-xL, FLAG-Bcl-xS, or Bcl-2 (green). Whereas both Bcl-xL and FLAG–Bcl-xS colocalize with the mitochondrial marker cytochrome c (Cyt.c, red), Bcl-2 colocalizes with the ER marker calnexin (red). Nuclei were stained with Hoechst 33342 (blue in the merge).
Figure 1.
Bcl-xL and Bcl-xS specifically localize to the MOM, whereas Bcl-2 resides on several membranes. (A) Anti–Bcl-2 and anti–Bcl-x Western blots of subcellular fractions from parental HEK 293 cells (endo) or HEK293 cells transiently overexpressing Bcl-2, Bcl-xL, or FLAG–Bcl-xS (exo). The mitochondrial fraction was obtained from the 1.4 M band and the heavy microsomal fraction from the 1.0 M band of the sucrose gradient (see Materials and methods). Light microsomes are the pellet of the 100,000 g spin. Purity of the fractions was checked with anti-grp78/Bip and anti-KDEL (microsomes) and anti–COX-VIc (mitochondria) antibodies. TAP(I-VI)–EGFP contains the first six membrane-spanning regions of the antigen peptide transporter I (TAP I) fused to EGFP. This protein specifically spans the ER membrane and is detected by anti-GFP Western blotting after transient transfection. (B) Anti–Bcl-x Western blots of mitochondrial matrix, inner membrane (mb), and outer membrane fractions of rat liver, HEK293 cells, and HEK293 cells transiently overexpressing Bcl-xL (HEK293/Bcl-xL). (C) Anti–Bcl-2 and anti–Bcl-x Western blots of mitochondria or microsomes from parental HEK293 cells or HEK293 cells overexpressing Bcl-2 or Bcl-xL or FLAG–Bcl-xS, extracted directly with detergent (total) or first treated with sodium carbonate (pH 12, peripheral) and then extracted with detergent (integral). (D) Autoradiography of [35S]methionine-labeled, in vitro–transcribed/translated (IVTT) Bcl-2, Bcl-xL, or FLAG–Bcl-xS inserted (alkali resistant, integral) or loosely attached (alkali extractable, peripheral) to mitochondria or microsomes (pellet), or remaining in the supernatant after spinning off the organelles. (E) Anti–Bcl-2 and anti–Bcl-x immunofluorescence analysis of R6 cells transiently overexpressing Bcl-xL, FLAG-Bcl-xS, or Bcl-2 (green). Whereas both Bcl-xL and FLAG–Bcl-xS colocalize with the mitochondrial marker cytochrome c (Cyt.c, red), Bcl-2 colocalizes with the ER marker calnexin (red). Nuclei were stained with Hoechst 33342 (blue in the merge).
Figure 1.
Bcl-xL and Bcl-xS specifically localize to the MOM, whereas Bcl-2 resides on several membranes. (A) Anti–Bcl-2 and anti–Bcl-x Western blots of subcellular fractions from parental HEK 293 cells (endo) or HEK293 cells transiently overexpressing Bcl-2, Bcl-xL, or FLAG–Bcl-xS (exo). The mitochondrial fraction was obtained from the 1.4 M band and the heavy microsomal fraction from the 1.0 M band of the sucrose gradient (see Materials and methods). Light microsomes are the pellet of the 100,000 g spin. Purity of the fractions was checked with anti-grp78/Bip and anti-KDEL (microsomes) and anti–COX-VIc (mitochondria) antibodies. TAP(I-VI)–EGFP contains the first six membrane-spanning regions of the antigen peptide transporter I (TAP I) fused to EGFP. This protein specifically spans the ER membrane and is detected by anti-GFP Western blotting after transient transfection. (B) Anti–Bcl-x Western blots of mitochondrial matrix, inner membrane (mb), and outer membrane fractions of rat liver, HEK293 cells, and HEK293 cells transiently overexpressing Bcl-xL (HEK293/Bcl-xL). (C) Anti–Bcl-2 and anti–Bcl-x Western blots of mitochondria or microsomes from parental HEK293 cells or HEK293 cells overexpressing Bcl-2 or Bcl-xL or FLAG–Bcl-xS, extracted directly with detergent (total) or first treated with sodium carbonate (pH 12, peripheral) and then extracted with detergent (integral). (D) Autoradiography of [35S]methionine-labeled, in vitro–transcribed/translated (IVTT) Bcl-2, Bcl-xL, or FLAG–Bcl-xS inserted (alkali resistant, integral) or loosely attached (alkali extractable, peripheral) to mitochondria or microsomes (pellet), or remaining in the supernatant after spinning off the organelles. (E) Anti–Bcl-2 and anti–Bcl-x immunofluorescence analysis of R6 cells transiently overexpressing Bcl-xL, FLAG-Bcl-xS, or Bcl-2 (green). Whereas both Bcl-xL and FLAG–Bcl-xS colocalize with the mitochondrial marker cytochrome c (Cyt.c, red), Bcl-2 colocalizes with the ER marker calnexin (red). Nuclei were stained with Hoechst 33342 (blue in the merge).
Figure 1.
Bcl-xL and Bcl-xS specifically localize to the MOM, whereas Bcl-2 resides on several membranes. (A) Anti–Bcl-2 and anti–Bcl-x Western blots of subcellular fractions from parental HEK 293 cells (endo) or HEK293 cells transiently overexpressing Bcl-2, Bcl-xL, or FLAG–Bcl-xS (exo). The mitochondrial fraction was obtained from the 1.4 M band and the heavy microsomal fraction from the 1.0 M band of the sucrose gradient (see Materials and methods). Light microsomes are the pellet of the 100,000 g spin. Purity of the fractions was checked with anti-grp78/Bip and anti-KDEL (microsomes) and anti–COX-VIc (mitochondria) antibodies. TAP(I-VI)–EGFP contains the first six membrane-spanning regions of the antigen peptide transporter I (TAP I) fused to EGFP. This protein specifically spans the ER membrane and is detected by anti-GFP Western blotting after transient transfection. (B) Anti–Bcl-x Western blots of mitochondrial matrix, inner membrane (mb), and outer membrane fractions of rat liver, HEK293 cells, and HEK293 cells transiently overexpressing Bcl-xL (HEK293/Bcl-xL). (C) Anti–Bcl-2 and anti–Bcl-x Western blots of mitochondria or microsomes from parental HEK293 cells or HEK293 cells overexpressing Bcl-2 or Bcl-xL or FLAG–Bcl-xS, extracted directly with detergent (total) or first treated with sodium carbonate (pH 12, peripheral) and then extracted with detergent (integral). (D) Autoradiography of [35S]methionine-labeled, in vitro–transcribed/translated (IVTT) Bcl-2, Bcl-xL, or FLAG–Bcl-xS inserted (alkali resistant, integral) or loosely attached (alkali extractable, peripheral) to mitochondria or microsomes (pellet), or remaining in the supernatant after spinning off the organelles. (E) Anti–Bcl-2 and anti–Bcl-x immunofluorescence analysis of R6 cells transiently overexpressing Bcl-xL, FLAG-Bcl-xS, or Bcl-2 (green). Whereas both Bcl-xL and FLAG–Bcl-xS colocalize with the mitochondrial marker cytochrome c (Cyt.c, red), Bcl-2 colocalizes with the ER marker calnexin (red). Nuclei were stained with Hoechst 33342 (blue in the merge).
Figure 2.
Schematic representation of Bcl-2, Bcl-xL, Bcl-xS, their mutants, and the EGFP fusion constructs. Schematic structure and amino acid sequences of (A) the COOH-terminal parts of wild-type Bcl-2 (yellow) and Bcl-xL/xS (blue), including the 19–amino acid-long TM domain, flanked by one to two basic amino acids at one end (B) and the X or X/2 domain (half of the X domain) at the other end (basic amino acids are numbered and indicated in bold); (B) the COOH-terminal parts of Bcl-2 and Bcl-xL/xS mutants (point mutations and insertions are underlined); (C) the COOH-terminal mutants of Bcl-2 and Bcl-x fused to the COOH terminus of EGFP.
Figure 2.
Schematic representation of Bcl-2, Bcl-xL, Bcl-xS, their mutants, and the EGFP fusion constructs. Schematic structure and amino acid sequences of (A) the COOH-terminal parts of wild-type Bcl-2 (yellow) and Bcl-xL/xS (blue), including the 19–amino acid-long TM domain, flanked by one to two basic amino acids at one end (B) and the X or X/2 domain (half of the X domain) at the other end (basic amino acids are numbered and indicated in bold); (B) the COOH-terminal parts of Bcl-2 and Bcl-xL/xS mutants (point mutations and insertions are underlined); (C) the COOH-terminal mutants of Bcl-2 and Bcl-x fused to the COOH terminus of EGFP.
Figure 2.
Schematic representation of Bcl-2, Bcl-xL, Bcl-xS, their mutants, and the EGFP fusion constructs. Schematic structure and amino acid sequences of (A) the COOH-terminal parts of wild-type Bcl-2 (yellow) and Bcl-xL/xS (blue), including the 19–amino acid-long TM domain, flanked by one to two basic amino acids at one end (B) and the X or X/2 domain (half of the X domain) at the other end (basic amino acids are numbered and indicated in bold); (B) the COOH-terminal parts of Bcl-2 and Bcl-xL/xS mutants (point mutations and insertions are underlined); (C) the COOH-terminal mutants of Bcl-2 and Bcl-x fused to the COOH terminus of EGFP.
Figure 3.
Tailless Bcl-x L and Bcl-2 mutants are cytoplasmic and partially attached to light microsomes. (A) Anti–Bcl-2 and anti–Bcl-x Western blots of subcellular fractions from HEK293 cells transiently transfected with Bcl-2 or Bcl-xL mutants lacking the last 21 amino acids (TMB domain) (Bcl-2ΔTMB and Bcl-xLΔTMB). In addition, a sodium carbonate (alkali) extraction of microsomes (as described in legend to Fig. 1 C) is shown for Bcl-2ΔTMB in the right panel. (B) Autoradiography of the IVTT products of Bcl-2ΔTMB, Bcl-xLΔTMB, and FLAG–Bcl-xsΔTMB, bound to microsomes (pellet) or remaining in the supernatant after spinning off the microsomes. (C) Anti–Bcl-2 and anti–Bcl-x immunofluorescence analysis of HeLa cells transiently overexpressing the three mutants.
Figure 3.
Tailless Bcl-x L and Bcl-2 mutants are cytoplasmic and partially attached to light microsomes. (A) Anti–Bcl-2 and anti–Bcl-x Western blots of subcellular fractions from HEK293 cells transiently transfected with Bcl-2 or Bcl-xL mutants lacking the last 21 amino acids (TMB domain) (Bcl-2ΔTMB and Bcl-xLΔTMB). In addition, a sodium carbonate (alkali) extraction of microsomes (as described in legend to Fig. 1 C) is shown for Bcl-2ΔTMB in the right panel. (B) Autoradiography of the IVTT products of Bcl-2ΔTMB, Bcl-xLΔTMB, and FLAG–Bcl-xsΔTMB, bound to microsomes (pellet) or remaining in the supernatant after spinning off the microsomes. (C) Anti–Bcl-2 and anti–Bcl-x immunofluorescence analysis of HeLa cells transiently overexpressing the three mutants.
Figure 3.
Tailless Bcl-x L and Bcl-2 mutants are cytoplasmic and partially attached to light microsomes. (A) Anti–Bcl-2 and anti–Bcl-x Western blots of subcellular fractions from HEK293 cells transiently transfected with Bcl-2 or Bcl-xL mutants lacking the last 21 amino acids (TMB domain) (Bcl-2ΔTMB and Bcl-xLΔTMB). In addition, a sodium carbonate (alkali) extraction of microsomes (as described in legend to Fig. 1 C) is shown for Bcl-2ΔTMB in the right panel. (B) Autoradiography of the IVTT products of Bcl-2ΔTMB, Bcl-xLΔTMB, and FLAG–Bcl-xsΔTMB, bound to microsomes (pellet) or remaining in the supernatant after spinning off the microsomes. (C) Anti–Bcl-2 and anti–Bcl-x immunofluorescence analysis of HeLa cells transiently overexpressing the three mutants.
Figure 4.
Two basic amino acids of the X domain and the TMB of Bcl-x compose a signal that targets EGFP to mitochondria. (A) Whole cell GFP fluorescence analysis of R6 cells transiently transfected with EGFP fused to various COOH-terminal mutants of Bcl-x and Bcl-2. The amino acid sequences of the mutants are described in Fig. 2 C. The mitochondrial colocalization marker is cytochrome c. Point mutations are underlined. (B) Anti-GFP Western blots of subcellular fractions from HEK293 cells expressing the various EGFP mutants. (C) Sodium carbonate extraction, as described in legend to Fig. 1 C, of mitochondria or microsomes isolated from HEK cells transfected with three selected EGFP mutants.
Figure 4.
Two basic amino acids of the X domain and the TMB of Bcl-x compose a signal that targets EGFP to mitochondria. (A) Whole cell GFP fluorescence analysis of R6 cells transiently transfected with EGFP fused to various COOH-terminal mutants of Bcl-x and Bcl-2. The amino acid sequences of the mutants are described in Fig. 2 C. The mitochondrial colocalization marker is cytochrome c. Point mutations are underlined. (B) Anti-GFP Western blots of subcellular fractions from HEK293 cells expressing the various EGFP mutants. (C) Sodium carbonate extraction, as described in legend to Fig. 1 C, of mitochondria or microsomes isolated from HEK cells transfected with three selected EGFP mutants.
Figure 4.
Two basic amino acids of the X domain and the TMB of Bcl-x compose a signal that targets EGFP to mitochondria. (A) Whole cell GFP fluorescence analysis of R6 cells transiently transfected with EGFP fused to various COOH-terminal mutants of Bcl-x and Bcl-2. The amino acid sequences of the mutants are described in Fig. 2 C. The mitochondrial colocalization marker is cytochrome c. Point mutations are underlined. (B) Anti-GFP Western blots of subcellular fractions from HEK293 cells expressing the various EGFP mutants. (C) Sodium carbonate extraction, as described in legend to Fig. 1 C, of mitochondria or microsomes isolated from HEK cells transfected with three selected EGFP mutants.
Figure 5.
Bcl-2 is specifically targeted to mitochondria upon acquisition of the X-TMB domain of Bcl-x. (A and B) Anti–Bcl-2 and anti–Bcl-x immunofluorescence analysis of HeLa cells transiently transfected with Bcl-2 and Bcl-xL chimera that had their X-TMB domains exchanged. The mitochondrial colocalization markers are cytochrome c or TOM20 as indicated. (C) Anti–Bcl-2 and anti–Bcl-x Western blots of subcellular fractions from HEK293 cells expressing the various chimeric mutants as well as a mutant of Bcl-xL devoid of its X domain (Bcl-xLΔX). An asterisk denotes the localization of endogenous Bcl-xL.
Figure 5.
Bcl-2 is specifically targeted to mitochondria upon acquisition of the X-TMB domain of Bcl-x. (A and B) Anti–Bcl-2 and anti–Bcl-x immunofluorescence analysis of HeLa cells transiently transfected with Bcl-2 and Bcl-xL chimera that had their X-TMB domains exchanged. The mitochondrial colocalization markers are cytochrome c or TOM20 as indicated. (C) Anti–Bcl-2 and anti–Bcl-x Western blots of subcellular fractions from HEK293 cells expressing the various chimeric mutants as well as a mutant of Bcl-xL devoid of its X domain (Bcl-xLΔX). An asterisk denotes the localization of endogenous Bcl-xL.
Figure 5.
Bcl-2 is specifically targeted to mitochondria upon acquisition of the X-TMB domain of Bcl-x. (A and B) Anti–Bcl-2 and anti–Bcl-x immunofluorescence analysis of HeLa cells transiently transfected with Bcl-2 and Bcl-xL chimera that had their X-TMB domains exchanged. The mitochondrial colocalization markers are cytochrome c or TOM20 as indicated. (C) Anti–Bcl-2 and anti–Bcl-x Western blots of subcellular fractions from HEK293 cells expressing the various chimeric mutants as well as a mutant of Bcl-xL devoid of its X domain (Bcl-xLΔX). An asterisk denotes the localization of endogenous Bcl-xL.
Figure 6.
MOM targeting also requires two basic residues downstream of the TM of Bcl-x and Bcl-2 accumulates on mitochondria by increasing the basicity surrounding its TM. (A and B) Anti–Bcl-2 and anti–Bcl-x immunofluorescence analysis of HeLa or R6 cells (as indicated) transiently transfected with FLAG-tagged Bcl-xL mutants that had their COOH-terminal basic residues exchanged to serines (A) or FLAG-tagged Bcl-2 mutants that contained additional basic residues at their COOH termini (B). In addition, the localization of COOH-terminal FLAG-tagged Bcl-xL is shown (Bcl-xL–FLAG). The mitochondrial colocalization markers are cytochrome c or TOM20 as indicated. (C) Anti-FLAG Western blots of subcellular fractions from HEK293 cells expressing the mutants described under A and B.
Figure 6.
MOM targeting also requires two basic residues downstream of the TM of Bcl-x and Bcl-2 accumulates on mitochondria by increasing the basicity surrounding its TM. (A and B) Anti–Bcl-2 and anti–Bcl-x immunofluorescence analysis of HeLa or R6 cells (as indicated) transiently transfected with FLAG-tagged Bcl-xL mutants that had their COOH-terminal basic residues exchanged to serines (A) or FLAG-tagged Bcl-2 mutants that contained additional basic residues at their COOH termini (B). In addition, the localization of COOH-terminal FLAG-tagged Bcl-xL is shown (Bcl-xL–FLAG). The mitochondrial colocalization markers are cytochrome c or TOM20 as indicated. (C) Anti-FLAG Western blots of subcellular fractions from HEK293 cells expressing the mutants described under A and B.
Figure 6.
MOM targeting also requires two basic residues downstream of the TM of Bcl-x and Bcl-2 accumulates on mitochondria by increasing the basicity surrounding its TM. (A and B) Anti–Bcl-2 and anti–Bcl-x immunofluorescence analysis of HeLa or R6 cells (as indicated) transiently transfected with FLAG-tagged Bcl-xL mutants that had their COOH-terminal basic residues exchanged to serines (A) or FLAG-tagged Bcl-2 mutants that contained additional basic residues at their COOH termini (B). In addition, the localization of COOH-terminal FLAG-tagged Bcl-xL is shown (Bcl-xL–FLAG). The mitochondrial colocalization markers are cytochrome c or TOM20 as indicated. (C) Anti-FLAG Western blots of subcellular fractions from HEK293 cells expressing the mutants described under A and B.
Figure 7.
Schematic representation of MOM- and ER-targeted proteins. (A) Amino acid sequences of MOM-targeted proteins whose COOH termini conform to the possible Bx0–9 Bx0–2-
TM
-x0–1 Bx0–6 B consensus sequence or contain a high basicity at one end of their TM-like FLAG–Bcl-2(HK
RK
) (TOM20 and Bcl-w). (B) Amino acid sequences of proteins that contain only one basic residues at each end (Bcl-2 and Mcl-1), or basic residues at only one end of the TM and thus localize to extra-mitochondrial sites.
Figure 7.
Schematic representation of MOM- and ER-targeted proteins. (A) Amino acid sequences of MOM-targeted proteins whose COOH termini conform to the possible Bx0–9 Bx0–2-
TM
-x0–1 Bx0–6 B consensus sequence or contain a high basicity at one end of their TM-like FLAG–Bcl-2(HK
RK
) (TOM20 and Bcl-w). (B) Amino acid sequences of proteins that contain only one basic residues at each end (Bcl-2 and Mcl-1), or basic residues at only one end of the TM and thus localize to extra-mitochondrial sites.
References
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