Back to Search
Start Over
By any means necessary: discovering a Bcl-xL specific domain
- Source :
- Journal of molecular biology. 427(6 Pt)
- Publication Year :
- 2015
-
Abstract
- The Bcl-2 family of proteins plays a critical role regulating apoptosis, and pro-survival Bcl-2 family members are important therapeutic targets due to their overexpression in different cancers. Pro-apoptotic BH3-only proteins antagonize pro-survival Bcl-2 protein functions by binding directly to them, and a sub-class of BH3-only proteins termed sensitizers can initiate apoptosis via this mechanism in response to diverse signals. The five pro-survival proteins Bcl-xL, Mcl-1, Bcl-2, Bcl-w and Bfl-1 differ in their binding preferences, with Bcl-xL, Bcl-2 and Bcl-w sharing similar interaction profiles for many natural sensitizers and small molecules. Peptides that bind selectively to just one or a subset of family members have shown utility in assays that diagnose apoptotic blockades in cancer cells and as reagents for dissecting apoptotic mechanism. Combining computational design, combinatorial library screening and rational mutagenesis, we designed a series of BH3 sensitizer peptides that bind Bcl-xL with sub-nanomolar affinity and selectivity up to 1000-fold over each of the four competing pro-survival proteins. We demonstrate the efficacy of our designed BH3 peptides in assays that differentiate between cancer cells that are dependent on different pro-survival proteins.
- Subjects :
- biology
Chemistry
bcl-X Protein
Bcl-xL
Breast Neoplasms
Computational biology
Apoptosis Regulatory Proteins
Peptide Fragments
Article
Domain (software engineering)
Proto-Oncogene Proteins c-bcl-2
Structural Biology
Peptide Library
biology.protein
Bcl x protein
Humans
Female
Peptide library
Molecular Biology
Subjects
Details
- ISSN :
- 10898638
- Volume :
- 427
- Issue :
- 6 Pt
- Database :
- OpenAIRE
- Journal :
- Journal of molecular biology
- Accession number :
- edsair.doi.dedup.....28aafc3409b113b87d8b092404ee2944