| Structural highlights
Disease
[BCL2_HUMAN] Note=A chromosomal aberration involving BCL2 has been found in chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions.
Function
[BCL2_HUMAN] Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1).[1] [B2L11_HUMAN] Induces apoptosis and anoikis. Isoform BimL is more potent than isoform BimEL. Isoform Bim-alpha1, isoform Bim-alpha2 and isoform Bim-alpha3 induce apoptosis, although less potent than isoform BimEL, isoform BimL and isoform BimS. Isoform Bim-gamma induces apoptosis. Isoform Bim-alpha3 induces apoptosis possibly through a caspase-mediated pathway. Isoform BimAC and isoform BimABC lack the ability to induce apoptosis.[2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
Peptides can be developed as effective antagonists of protein-protein interactions, but conventional peptides (i.e., oligomers of l-alpha-amino acids) suffer from significant limitations in vivo. Short half-lives due to rapid proteolytic degradation and an inability to cross cell membranes often preclude biological applications of peptides. Oligomers that contain both alpha- and beta-amino acid residues ("alpha/beta-peptides") manifest decreased susceptibility to proteolytic degradation, and when properly designed these unnatural oligomers can mimic the protein-recognition properties of analogous "alpha-peptides". This report documents an extension of the alpha/beta-peptide approach to target intracellular protein-protein interactions. Specifically, we have generated alpha/beta-peptides based on a "stapled" Bim BH3 alpha-peptide, which contains a hydrocarbon cross-link to enhance alpha-helix stability. We show that a stapled alpha/beta-peptide can structurally and functionally mimic the parent stapled alpha-peptide in its ability to enter certain types of cells and block protein-protein interactions associated with apoptotic signaling. However, the alpha/beta-peptide is nearly 100-fold more resistant to proteolysis than is the parent stapled alpha-peptide. These results show that backbone modification, a strategy that has received relatively little attention in terms of peptide engineering for biomedical applications, can be combined with more commonly deployed peripheral modifications such as side chain cross-linking to produce synergistic benefits.
alpha/beta-Peptide Foldamers Targeting Intracellular Protein-Protein Interactions with Activity in Living Cells.,Checco JW, Lee EF, Evangelista M, Sleebs NJ, Rogers K, Pettikiriarachchi A, Kershaw NJ, Eddinger GA, Belair DG, Wilson JL, Eller CH, Raines RT, Murphy WL, Smith BJ, Gellman SH, Fairlie WD J Am Chem Soc. 2015 Aug 28. PMID:26317395[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wei Y, Pattingre S, Sinha S, Bassik M, Levine B. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell. 2008 Jun 20;30(6):678-88. doi: 10.1016/j.molcel.2008.06.001. PMID:18570871 doi:10.1016/j.molcel.2008.06.001
- ↑ O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S, Huang DC. Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J. 1998 Jan 15;17(2):384-95. PMID:9430630 doi:http://dx.doi.org/10.1093/emboj/17.2.384
- ↑ U M, Miyashita T, Shikama Y, Tadokoro K, Yamada M. Molecular cloning and characterization of six novel isoforms of human Bim, a member of the proapoptotic Bcl-2 family. FEBS Lett. 2001 Nov 30;509(1):135-41. PMID:11734221
- ↑ Liu JW, Chandra D, Tang SH, Chopra D, Tang DG. Identification and characterization of Bimgamma, a novel proapoptotic BH3-only splice variant of Bim. Cancer Res. 2002 May 15;62(10):2976-81. PMID:12019181
- ↑ Marani M, Tenev T, Hancock D, Downward J, Lemoine NR. Identification of novel isoforms of the BH3 domain protein Bim which directly activate Bax to trigger apoptosis. Mol Cell Biol. 2002 Jun;22(11):3577-89. PMID:11997495
- ↑ Chen JZ, Ji CN, Gu SH, Li JX, Zhao EP, Huang Y, Huang L, Ying K, Xie Y, Mao YM. Over-expression of Bim alpha3, a novel isoform of human Bim, result in cell apoptosis. Int J Biochem Cell Biol. 2004 Aug;36(8):1554-61. PMID:15147734 doi:http://dx.doi.org/10.1016/j.biocel.2003.12.015
- ↑ Fukazawa H, Noguchi K, Masumi A, Murakami Y, Uehara Y. BimEL is an important determinant for induction of anoikis sensitivity by mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitors. Mol Cancer Ther. 2004 Oct;3(10):1281-8. PMID:15486195
- ↑ Checco JW, Lee EF, Evangelista M, Sleebs NJ, Rogers K, Pettikiriarachchi A, Kershaw NJ, Eddinger GA, Belair DG, Wilson JL, Eller CH, Raines RT, Murphy WL, Smith BJ, Gellman SH, Fairlie WD. alpha/beta-Peptide Foldamers Targeting Intracellular Protein-Protein Interactions with Activity in Living Cells. J Am Chem Soc. 2015 Aug 28. PMID:26317395 doi:http://dx.doi.org/10.1021/jacs.5b05896
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