The Incomplete Puzzle of the BCL2 Proteins

Abstract

The proteins of the BCL2 family are key players in multiple cellular processes, chief amongst them being the regulation of mitochondrial integrity and apoptotic cell death. These proteins establish an intricate interaction network that expands both the cytosol and the surface of organelles to dictate the cell fate. The complexity and unpredictability of the BCL2 interactome resides in the large number of family members and of interaction surfaces, as well as on their different behaviours in solution and in the membrane. Although our current structural knowledge of the BCL2 proteins has been proven therapeutically relevant, the precise structure of membrane-bound complexes and the regulatory effect that membrane lipids exert over these proteins remain key questions in the field. Here, we discuss the complexity of BCL2 interactome, the new insights, and the black matter in the field.

Nuclear‐mitochondrial crosstalk: On the role of the nuclear receptor liver receptor homolog‐1 (NR5A2) in the regulation of mitochondrial metabolism, cell survival, and cancer

“…In general, the Bcl-2 family can be subdivided into three groups: (a) antiapoptotic Bcl-2 proteins, including Bcl-2, Bcl-xL, and Mcl1, that counteract MOMP by binding to and thus inhibiting pro-apoptotic family members; (b) the pro-apoptotic effectors Bax and Bak, that upon activation integrate, oligomerize, and form pores in the mitochondrial outer membrane; (c) BH3-only proteins like Bim, Bid, Puma, and Noxa, which are direct activators of Bax/Bak and/or block antiapoptotic Bcl-2 family members. 111,112 Various signaling pathways regulate the relative abundance as well as activity of BH3-only proteins, making them important upstream sensors that fine-tune the antagonizing forces between antiapoptotic and pro-apoptotic Bcl-2 proteins during apoptotic signaling. Pro-and antisurvival signals are thus integrated by the highly complex interactome and balance of Bcl-2 family members, deciding over the cellular fate by controlling integrity of mitochondria.…”

Targeting Mitochondrial Apoptosis to Overcome Treatment Resistance in Cancer

“…The BH3 motif is composed of 9 to 15 amino acids and is uniquely conserved across all BCL-2 family members [16]. BH3 interactions are responsible for orchestrating the BCL-2 interactome via a BH3-into-hydrophobic groove mechanism [17,18], which allows the formation of homo-and heterodimers that control apoptotic function [19]. Minor alterations in the amino acid sequences of the binding grooves and BH3 domains control the specificity of these interactions.…”

“…Membrane insertion and BAX oligomerization are the rate limiting steps for intrinsic apoptosis to proceed. Changes in the mechanical properties of the mitochondrial membrane may regulate BCL-2 proteins, or the membrane itself may have direct effects in modulating BCL-2 family member function [19]. One study has reported increased resistance for BAX-BCL-xL complexes when membrane inserted, and it is proposed that the inhibition of BAX oligomerization by BCL-2 proteins in the context of cellular membranes may be an effective means to allow the cell to avoid BAX activation [167].…”

Regulation of Apoptosis by the Bcl-2 Family of Proteins: Field on a Brink

“…The current Special Issue of Cells , “Regulation of Apoptosis by the Bcl-2 Family of Proteins”, gives a sense of the recent advances in all aspects of apoptotic regulation, ranging from in vitro biophysical characterization, through in vivo cellular studies, to preclinical and clinical studies of cancer treatments. The contributions to this Special Issue include three original articles, employing sophisticated techniques to gain important insights into the mechanisms of apoptotic regulation [ 1 , 2 , 3 ]; a thought-provoking perspective article [ 4 ] and two conceptual reviews, discussing state-of-the-art developments in drugs targeting anti-apoptotic Bcl-2 proteins [ 5 , 6 ]. Despite the collection of articles not encompassing all aspects of apoptosis, the following two general themes can be clearly identified.…”

“…A major knowledge gap is, therefore, the lack of accurate molecular pictures of protein-lipid interactions, protein refolding on the membrane and protein–protein interactions in the context of membrane-refolded conformations. The perspective article by Flores-Romero and García-Sáez [ 4 ], entitled The Incomplete Puzzle of the BCL2 Proteins , provides a critical examination of the recent insights and remaining challenges in this excitingly complex field of Bcl-2 proteins. It concludes that “we still fail to understand the contribution of mitochondrial lipids in modulating their activation, oligomerization and formation of supramolecular structures at apoptotic foci during and after MOMP.” One step toward completing the outlined puzzle is presented by Vasquez-Montes and co-workers [ 3 ], who use a battery of spectroscopic tools including single-molecule Förster Resonance Energy Transfer to test the hypothesis of the lipid-dependent conformational switching in the apoptotic inhibitor Bcl-xL.…”