Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 284, Issue 45, Pages 31315-31326Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.048009
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Funding
- National Health and Medical Research Council of Australia (NHRMC) [461221]
- Leukemia and Lymphoma Society [SCOR 7015-02]
- Cancer Council of Victoria [461239]
- Leukemia Foundation of Australia Phillip Desbrow Post Doctoral Fellowship
- Australian Cancer Research Foundation
- NHMRC IRIISS [361646]
- Victorian State Government
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Interactions between Bcl-2 homology-3 (BH3)-only proteins and their pro-survival Bcl-2 family binding partners initiate the intrinsic apoptosis pathway. These interactions are mediated by a short helical motif, the BH3 domain, on the BH3-only protein, which inserts into a hydrophobic groove on the pro-survival molecule. To identify novel peptidic ligands that bind Mcl-1, a pro-survival protein relative of Bcl-2, both human and mouse Mcl-1 were screened against large randomized phage-displayed peptide libraries. We identified a number of 16-mer peptides with sub-micromolar affinity that were highly selective for Mcl-1, as well as being somewhat selective for the species of Mcl-1 (human or mouse) against which the library was panned. Interestingly, these sequences all strongly resembled natural BH3 domain sequences. By switching residues within the best of the human Mcl-1-binding sequences, or extending beyond the core sequence identified, we were able to alter the pro-survival protein interaction profile of this peptide such that it now bound all members tightly and was a potent killer when introduced into cells. Introduction of an amide lock constraint within this sequence also increased its helicity and binding to pro-survival proteins. These data provide new insights into the determinants of BH3 domain: pro-survival protein affinity and selectivity.
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