Abstract
B-cell lymphoma-2 (Bcl-2) proteins mediate intrinsic-, or mitochondrial-, initiated apoptosis. We have investigated the structure and function of the least characterized Bcl-2 family member, Bcl-B, solving the crystal structure of a Bcl-B:Bim complex to 1.9 Å resolution. Bcl-B is distinguished from other Bcl-2 family members through an insertion of an unstructured loop between helices α5 and α6. Probing Bcl-B interactions with Bcl-2 homology (BH)3 motifs using a combination of biophysical- and cell-based assays revealed a unique BH3-only protein binding profile. Bcl-B has high-affinity interactions with Bim and Bik only. Our results not only delineate the mode of action of Bcl-B but also complete our understanding of the specific interactions between BH3-only proteins and their prosurvival Bcl-2 counterparts. Notably, we conclude that Bim is the universal prosurvival antagonist as no other BH3-only protein binds all six prosurvival proteins and that Mcl-1 and Bcl-xL form a distinct prosurvival dyad.
Highlights
Multiple alignment of the non-redundant Bcl-B sequences against the other multimotif B-cell lymphoma-2 (Bcl-2) family members shows they cluster as a separate lineage, indicating that BclB derives from a common Bcl-2 ancestor
The a5–a6 insertion differentiates the mammalian sequences both from other Bcl-B sequences and other Bcl-2 proteins
Phylogenetic analysis of human Bcl-2 sequences shows that Bcl-B has diverged from other human Bcl-2 proteins and forms a distinct lineage (Supplementary Figure S5)
Summary
This sequence motif forms part of the BH3 binding site in the prosurvival Bcl-2 family and an N-terminal helix-capping motif at the initiation site of helix a5 that is highly conserved in the multimotif Bcl-2 family (including the proapoptotic proteins Bax, Bak and Bok).[30] In Bcl-B this sequence is TWGR and the side-chain hydroxyl oxygen of T83 provides the acceptor atom for a hydrogen bond with the donor amide of R86.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
