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Bid chimeras indicate that most BH3-only proteins can directly activate Bak and Bax, and show no preference for Bak versus Bax

Hockings, C., Anwari, K., Ninnis, R. L., Brouwer, J., O'Hely, M., Evangelista, M., Hinds, M. G., Czabotar, P. E., Lee, E. F., Fairlie, W. D., Dewson, G. and Kluck, R. M. 2015, Bid chimeras indicate that most BH3-only proteins can directly activate Bak and Bax, and show no preference for Bak versus Bax, Cell death and disease, vol. 6, pp. 1-8, doi: 10.1038/cddis.2015.105.

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Title Bid chimeras indicate that most BH3-only proteins can directly activate Bak and Bax, and show no preference for Bak versus Bax
Formatted title Bid chimeras indicate that most BH3-only proteins can directly activate Bak and Bax, and show no preference for Bak versus Bax
Author(s) Hockings, C.
Anwari, K.
Ninnis, R. L.
Brouwer, J.
O'Hely, M.
Evangelista, M.
Hinds, M. G.
Czabotar, P. E.
Lee, E. F.
Fairlie, W. D.
Dewson, G.
Kluck, R. M.
Journal name Cell death and disease
Volume number 6
Start page 1
End page 8
Total pages 8
Publisher Nature Publishing Group
Place of publication London, Eng.
Publication date 2015
ISSN 2041-4889
Keyword(s) Science & Technology
Life Sciences & Biomedicine
Cell Biology
PROSURVIVAL BCL-2 PROTEINS
CYTOCHROME-C RELEASE
BH3 DOMAINS
MEMBRANE PERMEABILIZATION
CELL-DEATH
MITOCHONDRIAL-MEMBRANE
APOPTOTIC FUNCTION
FAMILY
BINDING
LIGAND
Summary The mitochondrial pathway of apoptosis is initiated by Bcl-2 homology region 3 (BH3)-only members of the Bcl-2 protein family. On upregulation or activation, certain BH3-only proteins can directly bind and activate Bak and Bax to induce conformation change, oligomerization and pore formation in mitochondria. BH3-only proteins, with the exception of Bid, are intrinsically disordered and therefore, functional studies often utilize peptides based on just their BH3 domains. However, these reagents do not possess the hydrophobic membrane targeting domains found on the native BH3-only molecule. To generate each BH3-only protein as a recombinant protein that could efficiently target mitochondria, we developed recombinant Bid chimeras in which the BH3 domain was replaced with that of other BH3-only proteins (Bim, Puma, Noxa, Bad, Bmf, Bik and Hrk). The chimeras were stable following purification, and each immunoprecipitated with full-length Bcl-xL according to the specificity reported for the related BH3 peptide. When tested for activation of Bak and Bax in mitochondrial permeabilization assays, Bid chimeras were ~1000-fold more effective than the related BH3 peptides. BH3 sequences from Bid and Bim were the strongest activators, followed by Puma, Hrk, Bmf and Bik, while Bad and Noxa were not activators. Notably, chimeras and peptides showed no apparent preference for activating Bak or Bax. In addition, within the BH3 domain, the h0 position recently found to be important for Bax activation, was important also for Bak activation. Together, our data with full-length proteins indicate that most BH3-only proteins can directly activate both Bak and Bax.
Language eng
DOI 10.1038/cddis.2015.105
Field of Research 110106 Medical Biochemistry: Proteins and Peptides (incl Medical Proteomics)
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2015, Macmillan Publishers
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30080429

Document type: Journal Article
Collections: School of Medicine
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.