Metazoans and Intrinsic Apoptosis: An Evolutionary Analysis of the Bcl-2 Family

Abstract

The B-cell lymphoma-2 (Bcl-2) family is a group of genes regulating intrinsic apoptosis, a process controlling events such as development, homeostasis and the innate and adaptive immune responses in metazoans. In higher organisms, Bcl-2 proteins coordinate intrinsic apoptosis through their regulation of the integrity of the mitochondrial outer membrane; this function appears to have originated in the basal metazoans. Bcl-2 genes predate the cnidarian-bilaterian split and have been identified in porifera, placozoans and cnidarians but not ctenophores and some nematodes. The Bcl-2 family is composed of two groups of proteins, one with an α-helical Bcl-2 fold that has been identified in porifera, placozoans, cnidarians, and almost all higher bilaterians. The second group of proteins, the BH3-only group, has little sequence conservation and less well-defined structures and is found in cnidarians and most bilaterians, but not porifera or placozoans. Here we examine the evolutionary relationships between Bcl-2 proteins. We show that the structures of the Bcl-2-fold proteins are highly conserved over evolutionary time. Some metazoans such as the urochordate Oikopleura dioica have lost all Bcl-2 family members. This gene loss indicates that Bcl-2 regulated apoptosis is not an absolute requirement in metazoans, a finding mirrored in recent gene deletion studies in mice. Sequence analysis suggests that at least some Bcl-2 proteins lack the ability to bind BH3-only antagonists and therefore potentially have other non-apoptotic functions. By examining the foundations of the Bcl-2 regulated apoptosis, functional relationships may be clarified that allow us to understand the role of specific Bcl-2 proteins in evolution and disease.

Crystal Structures of Epstein–Barr Virus Bcl-2 Homolog BHRF1 Bound to Bid and Puma BH3 Motif Peptides

“…Among these, E89 and R100 formed ionic interactions, and R100 made the highly conserved canonical salt bridge interaction with the conserved aspartic acid residue from the BH3 motif. This salt bridge is a hallmark interaction between pro-survival Bcl-2 protein and the BH3 motif of proapoptotic Bcl-2 protein [ 9 ], conserved across evolution [ 52 , 53 ], also reported for the BHRF1–BimBH3 and BHRF1–BakBH3 complexes [ 18 ]. The BH1 motif is located at the N-terminus of α5, and, although it generally conforms to the sequence XXGR, where XX are most commonly NW, but may vary, with the GR dipeptide very strongly conserved.…”

Antiproliferative effect of Solanum nigrum L. water extract on breast cancer cells: potential roles of apoptosis and oxidative stress

“…To further investigate the apoptosis-mediated cell death by SNWE treatment we examined the role of BCL-2 family members including BAX, Caspase3 and p53. These BCL-2 family members play an important role in inducing the intrinsic pathway of apoptosis (49). In normal conditions, BAX is localized in the cytosol, when the apoptosis is induced it undergoes a conformational change and is translocated to mitochondria to release further apoptotic factors.…”

BCL-G: 20 years of research on a non-typical protein from the BCL-2 family

“…Although the phylogenetic tree of BCL-2 homologous proteins, rooted with CED-9 sequences from Caenorhabditis and including BCL-G, has been demonstrated [99], BCL-G remains understudied in this respect. In general, the phylogenetic analyses have revealed quite similar structures and mechanisms of interactions between BCL-2-like proteins despite their either convergent or divergent history of evolution [100][101][102][103][104][105][106][107]. In addition, as alternatively spliced variants lacking certain motifs are found in the family as exemplified by BCL-X S and BCL-G S , it has been speculated that some BCL-2-like proteins derive from a common ancestry with multidomain members through gene duplication and exon loss [108][109][110].…”