| Single-point mutations of a lysine residue change function of Bax and Bcl-xL expressed in Bax- and Bak-less mouse embryonic fibroblasts: novel insights into the molecular mechanisms of Bax-induced apoptosis. | |
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MedLine Citation:
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PMID: 20885444 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Members of the Bcl-2 family play key roles as proapoptotic (e.g., Bax) and antiapoptotic (e.g., Bcl-x(L)) regulators of programmed cell death. We previously identified the mitochondrial potassium channel Kv1.3 as a novel target of Bax. Incubating Kv1.3-positive isolated mitochondria with Bax triggered apoptotic events, whereas Kv1.3-deficient mitochondria were resistant to this stimulus. Mutation of Bax at lysine 128 (BaxK128E) abrogated its effects on Kv1.3 and the induction of apoptotic changes in mitochondria. These data indicate a toxin-like action of Bax on Kv1.3 to trigger at least some of the mitochondrial changes typical for apoptosis. To gain insight into the mechanism of Bax-Kv1.3 interaction, we mutated Glu158 of Bcl-x(L) (corresponding to K128 in Bax) to lysine. This substitution turned Bcl-x(L) proapoptotic. Transfection of double knockout (Bax(-/-)/Bak(-/-)) mouse embryonic fibroblasts (DKO MEFs) with either wild-type Bax, BaxK128E, or Bcl-x(L)E158K showed that apoptosis induced by various stimuli was defective in DKO MEFs and BaxK128E-transfected cells, but was recovered upon transfection with Bcl-xLE158K or wild-type Bax. Both wild-type Bax and BaxK128E can form similar ion-conducting pores upon incorporation into planar lipid bilayers. Our results point to a physiologically relevant interaction of Bax with Kv1.3 and further indicate a crucial role of a distinct lysine in determining the proapoptotic character of Bcl2-family proteins. |
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Authors:
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I Szabò; M Soddemann; L Leanza; M Zoratti; E Gulbins |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-10-01 |
Journal Detail:
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Title: Cell death and differentiation Volume: 18 ISSN: 1476-5403 ISO Abbreviation: Cell Death Differ. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-02-14 Completed Date: 2011-05-31 Revised Date: 2012-03-01 |
Medline Journal Info:
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Nlm Unique ID: 9437445 Medline TA: Cell Death Differ Country: England |
Other Details:
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Languages: eng Pagination: 427-38 Citation Subset: IM |
Affiliation:
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Department of Biology, University of Padova, Padova, Italy. ildi@civ.bio.unipd.it |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Animals Apoptosis / genetics* Cytochromes c / metabolism Embryo, Mammalian / cytology Fibroblasts / cytology*, metabolism Humans Ion Channel Gating Jurkat Cells Kv1.3 Potassium Channel / metabolism Lipid Bilayers / metabolism Lysine / genetics* Membrane Potential, Mitochondrial Mice Molecular Sequence Data Mutant Proteins / chemistry, metabolism Point Mutation / genetics* Protein Structure, Quaternary Sequence Homology, Amino Acid bcl-2 Homologous Antagonist-Killer Protein / chemistry, deficiency*, metabolism bcl-2-Associated X Protein / chemistry, deficiency, genetics*, metabolism bcl-X Protein / chemistry, genetics*, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Kv1.3 Potassium Channel; 0/Lipid Bilayers; 0/Mutant Proteins; 0/bcl-2 Homologous Antagonist-Killer Protein; 0/bcl-2-Associated X Protein; 0/bcl-X Protein; 56-87-1/Lysine; 9007-43-6/Cytochromes c |
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