Bax contains two functional mitochondrial targeting sequences and translocates to mitochondria in a conformational change- and homo-oligomerization-driven process.
The apoptosis gateway protein Bax normally exists in the cytosol as a globular shaped monomer composed of nine alpha-helices. During apoptosis, Bax translocates to the mitochondria, forms homo-oligomers, and subsequently induces mitochondrial damage. The mechanism of Bax mitochondrial translocation remains unclear. Among the nine alpha-helices of Bax, helices 4, 5, 6, and 9 are capable of targeting a heterologous protein to mitochondria. However, only helices 6 and 9 can independently direct the oligomerized Bax to the mitochondria. Although Bax mitochondrial translocation can still proceed with mutations in either helix 6 or helix 9, combined mutations completely abolished mitochondrial targeting in response to activating signals. Using a proline mutagenesis scanning analysis, we demonstrated that conformational changes were sufficient to cause Bax to move from the cytosol to the mitochondria. Moreover, we found that homo-oligomerization of Bax contributed to its mitochondrial translocation. These results suggest that Bax is targeted to the mitochondria through the exposure of one or both of the two functional mitochondrial targeting sequences in a conformational change-driven and homo-oligomerization-aided process.
George
Nicholas M
NM
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-7696, USA.
Targy
Natalie
N
Evans
Jacquelynn J D
JJ
Zhang
Liqiang
L
Luo
Xu
X
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D021382:Protein Sorting Signals / Q000502:physiology*; D020836:Protein Structure, Quaternary / Q000502:physiology; D017433:Protein Structure, Secondary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
C494826:BAX protein, human; C494827:Bax protein, mouse; D021382:Protein Sorting Signals; D051028:bcl-2-Associated X Protein