PROSITE documentation PDOC00829

Apoptosis regulator proteins, Bcl-2 family BH motifs signatures/profiles

Active cell suicide (apoptosis) is induced by events such as growth factor withdrawal and toxins. It is controlled by regulators, which have either an inhibitory effect on programmed cell death (anti-apoptotic) or block the protective effect of inhibitors (pro-apoptotic) [1,2]. Many viruses have found a way of countering defensive apoptosis by encoding their own anti-apoptosis genes preventing their target-cells from dying too soon.

All proteins belonging to the Bcl-2 family [3] contain either a BH1, BH2, BH3, or BH4 motif. All anti-apoptotic proteins contain BH1 and BH2 motifs; some of them contain an additional N-terminal BH4 motif (Bcl-2, Bcl-x(L), Bcl-w), which is never seen in pro-apoptotic proteins, except for Bcl-x(S). On the other hand, all pro-apoptotic proteins contain a BH3 motif (except for Bad) necessary for dimerization with other proteins of Bcl-2 family and crucial for their killing activity; some of them also contain BH1 and BH2 motifs (Bax, Bak). The BH3 motif is also present in some anti-apoptotic protein, such as Bcl-2 or Bcl-x(L).

Some proteins that are known to contain these motifs are listed below.

• Vertebrate protein Bcl-2. Bcl-2 blocks apoptosis; it prolongs the survival of hematopoietic cells in the absence of required growth factors and also in the presence of various stimuli inducing cellular death. Two isoforms of bcl-2 (α and β) are generated by alternative splicing. Bcl-2 is expressed in a wide range of tissues at various times during development. It forms heterodimers with the Bax proteins.
• Vertebrate protein Bcl-x. Two isoforms of Bcl-x (Bcl-x(L) and Bcl-x(S)) are generated by alternative splicing. While the longer product (Bcl-x(L)) can protect a growth-factor-dependent cell line from apoptosis, the shorter form blocks the protective effect of Bcl-2 and Bcl-x(L) and acts as an anti-anti-apoptosis protein.
• Mammalian protein Bax. Bax block the anti-apoptosis ability of Bcl-2 with which it forms heterodimers. There is no evidence that Bax has any activity in the absence of Bcl-2. Three isoforms of bax (α, β and γ) are generated by alternative splicing.
• Mammalian protein Bak, which promotes cell death and counteracts the protection from apoptosis provided by Bcl-2.
• Mammalian protein Bcl-w, which promotes cell survival.
• Mammalian protein bad, which promotes cell death, and counteracts the protection from apoptosis provided by Bcl-x(L), but not that of Bcl-2.
• Human protein Bik, which promotes cell death, but cannot counteracts the protection from apoptosis provided by Bcl-2.
• Mouse protein Bid, which induces caspases and apoptosis, and counteracts the protection from apoptosis provided by Bcl-2.
• Xenopus laevis protein Xr1, which could be the homolog of mammalian Bcl-w.
• Xenopus laevis protein Xr11, which promotes cell survival.
• Human induced myeloid leukemia cell differentiation protein MCL1. MCL1 is probably involved in programming of differentiation and concomitant maintenance of viability but not proliferation. Its expression increases early during phorbolester induced differentiation in myeloid leukemia cell line ML-1.
• Mouse hemopoietic-specific early response protein A1.
• African swine fever virus protein LMW5-HL, a bcl-2 homolog expressed early and late in the infection cycle. It also shows similarity to the Epstein- Barr-Virus (EBV) BHRF1, which is distantly related to the Bcl-2 family and is therefore not discussed in this entry.
• Caenorhabditis protein ced-9 [2].
• Mammalian activator of apoptosis Harakiri [4] (also known as neuronal death protein Dp5). This is a small protein of 92 residues that activates apoptosis. It contains a BH3 motif, but no BH1, BH2 or BH4 motifs.

We have developed patterns for the four BH motifs. There is also a profile for the BH4 motif as well as one profile for the bcl-2 family that spans part of BH3, BH1 and BH2 motifs.