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Publication Abstract from PubMed

Sponges of the porifera family harbor some of the evolutionary most ancient orthologs of the B-cell lymphoma-2 (Bcl-2) family, a protein family critical to regulation of apoptosis. The genome of the sponge Geodia cydonium contains the putative pro-survival Bcl-2 homolog BHP2, which protects sponge tissue as well as mammalian Hek-293 and NIH-3T3 cells against diverse apoptotic stimuli. The Lake Baikal demosponge Lubomirskia baicalensis has been shown to encode both putative pro-survival Bcl-2 (LB-Bcl-2) and pro-apoptotic Bcl-2 members (LB-Bak-2), which have been implied in axis formation (branches) in L. baicalensis. However, the molecular mechanism of action of sponge-encoded orthologs of Bcl-2 remains to be clarified. Here, we report that the pro-survival Bcl-2 ortholog BHP2 from G. cydonium is able to bind the BH3 motif of a pro-apoptotic Bcl-2 protein, LB-Bak-2 of the sponge L. baicalensis. Furthermore, we determined the crystal structure of BHP2 bound to LB-Bak-2, which revealed that using a binding groove conserved across all pro-survival Bcl-2 proteins, BHP2 binds multi-motif Bax-like proteins through their BH3-binding regions. However, BHP2 discriminates against BH3-only bearing proteins by blocking access to a hydrophobic pocket that is critical for BH3 motif binding in pro-survival Bcl-2 proteins from higher organisms. This differential binding mode is reflected in a structure-based phylogenetic comparison of BHP2 with other Bcl-2 family members, which revealed that BHP2 does not cluster with either Bcl-2 members of higher organisms or pathogen-encoded homologs, and assumes a discrete position. Our findings suggest that the molecular machinery and mechanisms for executing Bcl-2-mediated apoptosis as observed in mammals are evolutionary ancient, with early regulation of apoptotic machineries closely resembling their modern counterparts in mammals rather than Caenorhabditis elegans or drosophila.

Structural insight into an evolutionarily ancient programmed cell death regulator - the crystal structure of marine sponge BHP2 bound to LB-Bak-2.,Caria S, Hinds MG, Kvansakul M Cell Death Dis. 2017 Jan 12;8(1):e2543. doi: 10.1038/cddis.2016.469. PMID:28079890^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.